4-Oxoquinoline compound and use thereof as HIV integrase inhibitor

ABSTRACT

An anti-HIV agent containing, as an active ingredient, a 4-oxoquinoline compound represented by the following formula [I] 
                 
wherein each symbol is as defined in the specification, or a pharmaceutically acceptable salt thereof. The compound of the present invention has HIV integrase inhibitory action and is useful as an anti-HIV agent for the prophylaxis or therapy of AIDS. Moreover, by a combined use with other anti-HIV agents such as protease inhibitors, reverse transcriptase inhibitors and the like, the compound can become a more effective anti-HIV agent. Since the compound has high inhibitory activity specific for integrases, it can provide a safe pharmaceutical agent with a fewer side effects for human.

TECHNICAL FIELD

The present invention relates to a novel 4-oxoquinoline compound usefulas an anti-HIV agent and a pharmaceutically acceptable salt thereof. Thepresent invention also relates to a novel use of a certain4-oxoquinoline compound and a pharmaceutically acceptable salt thereofas anti-HIV agents. More particularly, the present invention relates toan anti-HIV agent containing a 4-oxoquinoline compound that particularlyshows an anti-HIV action based on an integrase inhibitory activitythereof, or a pharmaceutically acceptable salt thereof.

BACKGROUND ART

HIV (Human Immunodeficiency Virus (type 1)) belonging to retrovirus is acausative virus of AIDS (Acquired Immunodeficiency Syndrome).

HIV targets CD4 positive cell groups such as helper T cell, macrophageand dendritic cell and destroys these immunocompetent cells to causeimmunodeficiency.

Accordingly, a pharmaceutical agent that eradicates HIV in the body orsuppresses its growth is effective for the treatment or prophylaxis ofAIDS.

HIV possesses a bimolecular RNA gene in a core protein, and which iscovered with an envelope protein. The RNA codes for several enzymes(protease, reverse transcriptase, integrase) characteristic of the virusand the like, and has translated reverse transcriptase and integrase inthe core, as well as protease inside and outside the core.

HIV attaches to and invades a host cell, causes uncoating, and releasesa complex of RNA and integrase, and the like into the cytoplasm. Fromthe RNA, DNA is transcribed by reverse transcriptase, and a full lengthdouble stranded DNA is produced. The DNA is imported into the nucleus ofthe host cell and integrated by integrase into the DNA of the host cell.The integrated DNA is converted to an mRNA by polymerase of the hostcell, from which mRNA various proteins necessary for forming a virus aresynthesized by HIV protease and the like, and a virus particle isfinally formed, which then undergoes budding and its release.

These virus specific enzymes are considered to be essential for thegrowth of HIV. These enzymes are drawing attention as the target of thedevelopment of antiviral agents, and several anti-HIV agents have beenalready developed.

For example, zidovudine, didanosine, lamivudine and the like have beenalready on the market as reverse transcriptase inhibitors, andindinavir, nelfinavir and the like as protease inhibitors.

In addition, a multiple drug combination therapy concurrently usingthese pharmaceutical agents has been employed. For example, a combineduse of two reverse transcriptase inhibitors (zidovudine and didanosine),and a combined use of three agents of reverse transcriptase inhibitors(zidovudine and lamivudine) and a protease inhibitor (nelfinavir) andthe like have been clinically applied. Such multiple drug combinationtherapy is becoming a mainstream of AIDS therapy (see, e.g., Guidelinesfor the Use of Antiretroviral Agents in HIV-Infected Adults andAdlescent. Aug. 13, 2001).

However, some of these pharmaceutical agents are known to cause sideeffects such as liver function failure, central nervous disorders (e.g.,vertigo), and the like. In addition, acquisition of resistance to apharmaceutical agent causes a problem. Even worse, emergence of an HIVthat shows multiple drug resistance in a multiple drug combinationtherapy has been known.

Under the circumstances, a further development of a novel pharmaceuticalagent, particularly a development of an anti-HIV agent based on a newmechanism, has been desired, wherein a development of an anti-HIV agenthaving an integrase inhibitory activity is expected, because anintegrase characteristic of retrovirus is an essential enzyme for thegrowth of HIV.

Nevertheless, an effective integrase inhibitor has not been found asyet.

Known compounds comparatively similar to the anti-HIV agent of thepresent invention are described in the following.

WO02/0704865 describes the following compounds [A], [B] and the like asanti-HIV agents having an integrase inhibitory activity (seeWO02/0704865 p. 118, Example I-62, p. 203, Example I-152).

In addition, WO02/36734 describes the following compound [C] and thelike as anti-HIV agents having an integrase inhibitory activity (seeWO02/36734, p. 106, Ex. 3).

Moreover, WO02/55079 describes the following compound [D] and the likeas anti-HIV agents having an integrase inhibitory activity (seeWO02/055079, p. 79, Ex. 1).

However, these publications do not include the 4-oxoquinoline compounddisclosed in the present specification, or any description suggestivethereof.

The compounds comparatively similar to the compound of the presentinvention are described in the following.

U.S. Pat. No. 3,472,859 describes the following compound [E] and thelike as antibacterial agents or antimicrobial agents (see U.S. Pat. No.3,472,859, column 11, line 10).

In addition, JP-A-48-26772 describes the following compound [F] and thelike as compounds having an antibacterial activity (see, e.g.,JP-A-48-26772, p. 6, Example 9; KYUSHU KYORITSU UNIVERSITY, MemoirsDepartment of Engineering, No. 14, pp. 21-32, March 1990; Memoirs KyushuInst. Tech. (Eng.) No. 14, pp. 13-16, 1984).

As dehydrogenase inhibitors, moreover, the following compound [G] andthe like have been pharmacologically evaluated (see Journal of MedicinalChemistry, table 1, vol. 15, No. 3, pp. 235-237, 1972).

In addition, JP-A-2002-534416 (patent family: WO0/40561, U.S. Pat. No.6,248,739, EP1140850) describes the following compound [H] and the likeas synthetic intermediates for compounds having an antiviral activity(see JP-A-2002-534416, p. 141, compound 60).

JP-A-2002-534417 (patent family: WO00/40563, U.S. Pat. No. 6,248,736,EP1140851) also describes the following compound [J] and the like assynthetic intermediates for compounds having an antiviral activity (seeJP-A-2002-534417, p. 34, compound 18).

Moreover, WO01/98275 (patent family: US20011103220) also describes thefollowing compound [K] and the like as synthetic intermediates forcompounds having an antiviral activity (see WO01/98275, p. 39, line 29).

Furthermore, JP-A-4-360872 (patent family: U.S. Pat. No. 5,985,894,EP498721B1) describes the following compound [L] and the like ascompounds having an antagonistic action against anti-angiotensin IIreceptor (see JP-A-4-360872, p. 64, Table 1)).

DISCLOSURE OF THE INVENTION

From the findings based on the pharmacological researches and clinicalresults obtained so far, an anti-HIV agent is effective for theprophylaxis of the onset of AIDS and the treatment thereof, andparticularly a compound having an integrase inhibitory action canprovide an effective anti-HIV agent.

It is therefore an object of the present invention to provide apharmaceutical agent having an anti-HIV action, particularly apharmaceutical agent having an integrase inhibitory action.

The present inventors have conducted intensive studies in an attempt tofind a compound having an anti-HIV action, particularly a compoundhaving an integrase inhibitory action, and completed the presentinvention.

Accordingly, the present invention is shown in the following (1) to(41).

(1) An anti-HIV agent containing a 4-oxoquinoline compound representedby the following formula [I] or a pharmaceutically acceptable saltthereof as an active ingredient:

wherein

-   -   ring Cy is a C₃₋₁₀ carbon ring group optionally substituted by 1        to 5 substituents selected from the following group A or a        heterocyclic group optionally substituted by 1 to 5 substituents        selected from the following group A        -   wherein the heterocyclic group is a saturated or unsaturated            ring containing, besides carbon atom(s), at least one            heteroatom selected from a nitrogen atom, an oxygen atom and            a sulfur atom, group A is a group consisting of cyano group,            phenyl group, nitro group, halogen atom, C₁₋₄ alkyl group,            halo C₁₋₄ alkyl group, halo C₁₋₄ alkyloxy group, —OR^(a1),            —SR^(a1), —NR^(a1)R^(a2), —CONR^(a1)R^(a2),            —SO₂NR^(a1)R^(a2), —COR^(a3), —NR^(a1)COR^(a3), —SO₂R^(a3),            —NR^(a1)SO₂R^(a3), —COOR^(a1) and —NR^(a2)COOR^(a3)            -   wherein R^(a1) and R^(a2) are the same or different and                each is hydrogen atom, C₁₋₄ alkyl group or benzyl group                and R^(a3) is C₁₋₄ alkyl group;    -   R¹ is a substituent selected from the following group B or a        C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituents        selected from halogen atom and the following group B        -   wherein group B is a group consisting of C₃₋₁₀ carbon ring            group optionally substituted by 1 to 5 substituents selected            from the above-mentioned group A, heterocyclic group (as            defined above) optionally substituted by 1 to 5 substituents            selected from the above-mentioned group A, —OR^(a4),            —SR^(a4), —NR^(a4)R^(a5), —CONR^(a4)R^(a5),            —SO₂NR^(a4)R^(a5), —COR^(a6), —NR^(a4)COR^(a6), —SO₂R^(a6),            —NR^(a4)SO₂R^(a6), —COOR^(a4) and —NR^(a5)COOR^(a6)            -   wherein R^(a4) and R^(a5) are the same or different and                each is hydrogen atom, C₁₋₄ alkyl group, C₃₋₁₀ carbon                ring group optionally substituted by 1 to 5 substituents                selected from the above-mentioned group A or                heterocyclic group (as defined above) optionally                substituted by 1 to 5 substituents selected from the                above-mentioned group A, and R^(a6) is C₁₋₄ alkyl group,                C₃₋₁₀ carbon ring group optionally substituted by 1 to 5                substituents selected from the above-mentioned group A                or heterocyclic group (as defined above) optionally                substituted by 1 to 5 substituents selected from the                above-mentioned group A;    -   R² is a hydrogen atom or a C₁₋₄ alkyl group;    -   R³¹ is a hydrogen atom, a cyano group, a hydroxy group, an amino        group, a nitro group, a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄        alkoxy group, a C₁₋₄ alkylsulfanyl group, a halo C₁₋₄ alkyl        group or a halo C₁₋₄ alkyloxy group;    -   X is a C—R³² or a nitrogen atom; and    -   Y is a C—R³³ or a nitrogen atom and        -   wherein R³² and R³³ are the same or different and each is            hydrogen atom, cyano group, nitro group, halogen atom, C₃₋₁₀            carbon ring group optionally substituted by 1 to 5            substituents selected from the above-mentioned group A,            heterocyclic group (as defined above) optionally substituted            by 1 to 5 substituents selected from the above-mentioned            group A or C₁₋₁₀ alkyl group optionally substituted by 1 to            3 substituents selected from halogen atom and the            above-mentioned group B, —OR^(a7), —SR^(a7), —NR^(a7)R^(a8),            —NR^(a7)COR^(a9), —COOR^(a10) or —N═CH—NR^(a10)R^(a11)            -   wherein R^(a7) and R^(a8) are the same or different and                each is hydrogen atom, group B or C₁₋₁₀ alkyl group                optionally substituted by 1 to 3 substituents selected                from halogen atom and the above-mentioned group B,                R^(a9) is C₁₋₄ alkyl group, and R^(a10) and R^(a11) are                the same or different and each is hydrogen atom or C₁₋₄                alkyl group.

(2) The anti-HIV agent of the above-mentioned (1), wherein X is C—R³²and Y is C—R³³.

(3) The anti-HIV agent of the above-mentioned (1), wherein ring Cy is

wherein

-   -   R⁴ and R⁶ are the same or different and each is a substituent        selected from the following group A        -   wherein group A is a group consisting of cyano group, phenyl            group, nitro group, halogen atom, C₁₋₄alkyl group, halo C₁₋₄            alkyl group, halo C₁₋₄ alkyloxy group, —OR^(a1), —SR^(a1),            —NR^(a1)R^(a2), —CONR^(a1)R^(a2), —SO₂NR^(a1)R^(a2),            —COR^(a3), —NR^(a1)COR^(a3), —SO₂R^(a3), —NR^(a1)R^(a3),            —COOR^(a1) and —NR^(a2)COOR^(a3)            -   wherein R^(a1) and R^(a2) are the same or different and                each is hydrogen atom, C₁₋₄ alkyl group or benzyl group                and R^(a3) is C₁₋₄ alkyl group;    -   R⁵ is a substituent selected from hydrogen atom and group A, and        R⁴ and R⁵ may form a fused ring together with a benzene ring        they substitute; and    -   m is 0 or an integer of 1 to 3, and when m is 2 or 3, then R⁶ of        each m may be the same or different.

(4) The anti-HIV agent of the above-mentioned (1), wherein R² is ahydrogen atom.

(5) A 4-oxoquinoline compound represented by the following formula [II]or a pharmaceutically acceptable salt thereof:

wherein

-   -   R⁴ and R⁶ are the same or different and each is a substituent        selected from the following group A        -   wherein group A is a group consisting of cyano group, phenyl            group, nitro group, halogen atom, C₁₋₄ alkyl group, halo            C₁₋₄ alkyl group, halo C₁₋₄ alkyloxy group, —OR^(a1),            —SR^(a1), —NR^(a1)R^(a2), —CONR^(a1)R^(a2),            —SO₂NR^(a1)R^(a2), —COR^(a3), —NR^(a1)COR^(a3), —SO₂R^(a3),            —NR^(a1)SO₂R^(a3), —COOR^(a1) and NR^(a2)COOR^(a3)            -   wherein R^(a1) and R^(a2) are the same or different and                each is hydrogen atom, C₁₋₄ alkyl group or benzyl group                and R^(a3) is C₁₋₄ alkyl group;    -   R⁵ is a substituent selected from hydrogen atom and the        above-mentioned group A, and R⁴ and R⁵ may form a fused ring        together with a benzene ring they substitute;    -   m is 0 or an integer of 1 to 3, and when m is 2 or 3, then R⁶ of        each m may be the same or different;    -   R¹ is a substituent selected from the following group B or a        C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituents        selected from halogen atom and the following group B        -   wherein group B is a group consisting of C₃₋₁₀ carbon ring            group optionally substituted by 1 to 5 substituents selected            from the above-mentioned group A, heterocyclic group            (wherein the heterocyclic group is a saturated or            unsaturated ring containing, besides carbon atom(s), at            least one heteroatom selected from a nitrogen atom, an            oxygen atom and a sulfur atom as defined above) optionally            substituted by 1 to 5 substituents selected from the            above-mentioned group A, —OR^(a4), —SR^(a4), —NR^(a4)R^(a5),            —CONR^(a4)R^(a5), —SO₂NR^(a4)R^(a5), —COR^(a6),            —NR^(a4)COR^(a6), —SO₂R^(a6), —NR^(a4)SO₂R^(a6), —COOR^(a4)            and —NR^(a5)COOR^(a6)            -   wherein R^(a4) and R^(a5) are the same or different and                each is hydrogen atom, C₁₋₄ alkyl group, C₃₋₁₀ carbon                ring group optionally substituted by 1 to 5 substituents                selected from the above-mentioned group A or                heterocyclic group (as defined above) optionally                substituted by 1 to 5 substituents selected from the                above-mentioned group A, and R^(a6) is C₁₋₄ alkyl group,                C₃₋₁₀ carbon ring group optionally substituted by 1 to 5                substituents selected from the above-mentioned group A                or heterocyclic group (as defined above) optionally                substituted by 1 to 5 substituents selected from the                above-mentioned group A;    -   R³¹ is a hydrogen atom, a cyano group, a hydroxy group, an amino        group, a nitro group, a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄        alkoxy group, a C₁₋₄ alkylsulfanyl group, a halo C₁₋₄ alkyl        group or a halo C₁₋₄ alkyloxy group; and    -   R³² and R³³ are the same or different and each is a hydrogen        atom, a cyano group, a nitro group, a halogen atom, a C₃₋₁₀        carbon ring group optionally substituted by 1 to 5 substituents        selected from the above-mentioned group A, a heterocyclic group        (as defined above) optionally substituted by 1 to 5 substituents        selected from the above-mentioned group A, C₁₋₁₀ alkyl group        optionally substituted by 1 to 3 substituents selected from        halogen atom and the above-mentioned group B, OR^(a7), —SR^(a7),        —NR^(a7)R^(a8), —NR^(a7)COR^(a9), —COOR^(a10) or        —N═CH—NR^(a10)R^(a11)        -   wherein R^(a7) and R^(a8) are the sa me or different and            each is hydrogen atom, group B or C₁₋₁₀ alkyl group            optionally substituted by 1 to 3 substituents selected from            halogen atom and the above-mentioned group B, R^(a9) is C₁₋₄            alkyl group, and R^(a10) and R^(a11) are the same or            different and each is hydrogen atom or C₁₋₄ alkyl group.

(6) The 4-oxoquinoline compound of the above-mentioned (5), wherein R³¹is a hydrogen atom, a cyano group, a hydroxy group or a C₁₋₄ alkoxygroup, or a pharmaceutically acceptable salt thereof.

(7) The 4-oxoquinoline compound of the above-mentioned (6), wherein R³¹is a hydrogen atom, or a pharmaceutically acceptable salt thereof.

(8) The 4-oxoquinoline compound of the above-mentioned (5), wherein

-   -   R³² and R³³ are the same or different and each is a hydrogen        atom, a cyano group, a halogen atom, a heterocyclic group        optionally substituted by 1 to 5 substituents selected from the        following group A        -   wherein the heterocyclic group is a saturated or unsaturated            ring containing, besides carbon atom(s), at least one            heteroatom selected from a nitrogen atom, an oxygen atom and            a sulfur atom and group A is a group consisting of cyano            group, phenyl group, nitro group, halogen atom, C₁₋₄ alkyl            group, halo C₁₋₄ alkyl group, halo C₁₋₄ alkyloxy group,            —OR^(a1), —SR^(a1), —NR^(a1)R^(a2), —CONR^(a1)R^(a2),            —SO₂NR^(a1)R^(a2), —COR^(a3), —NR^(a1)COR^(a3), —SO₂R^(a3),            —NR^(a1)SO₂R^(a3), —COOR^(a1) and —NR^(a2)COOR^(a3)            -   wherein R^(a1) and R^(a2) are the same or different and                each is hydrogen atom C₁₋₄ alkyl group or benzyl group                and R^(a3) is C₁₋₄ alkyl group,        -   a C₁₋₁₀ alkyl group optionally substituted by 1 to 3            substituents selected from halogen atom and the following            group B            -   wherein group B is a group consisting of C₃₋₁₀ carbon                ring group optionally substituted by 1 to 5 substituents                selected from the above-mentioned group A, heterocyclic                group (as defined above) optionally substituted by 1 to                5 substituents selected from the above-mentioned group                A, —OR^(a4), —SR^(a4), —NR^(4a)R^(a5), —CONR^(a4)R^(a5),                —SO₂NR^(a4)R^(a5), —COR^(a6), —NR^(a4)COR^(a6),                —SO₂R^(a6), —NR^(a4)SO₂R^(a6), —COOR^(a4) and                —NR^(a5)COOR^(a6)                -   wherein R^(a4) and R^(a5) are the same or different                    and each is hydrogen atom, C₁₋₄ alkyl group, C₃₋₁₀                    carbon ring group optionally substituted by 1 to 5                    substituents selected from the above-mentioned group                    A or heterocyclic group (as defined above)                    optionally substituted by 1 to 5 substituents                    selected from the above-mentioned group A, and                    R^(a6) is C₁₋₄ alkyl group, C₃₋₁₀ carbon ring group                    optionally substituted by 1 to 5 substituents                    selected from the above-mentioned group A or                    heterocyclic group (as defined above) optionally                    substituted by 1 to 5 substituents selected from the                    above-mentioned group A,            -   —OR^(a7), —SR^(a7), —NR^(a7)R^(a8), —NR^(a7)COR^(a9),                —COOR^(a10) or —N═CH—NR^(a10)R^(a11)                -   wherein R^(a7) and R^(a8) are the same or different                    and each is hydrogen atom, group B or C₁₋₁₀ alkyl                    group optionally substituted by 1 to 3 substituents                    selected from halogen atom and the above-mentioned                    group B, R^(a9) is C₁₋₄ alkyl group, and R^(a10) and                    R^(a11) are the same or different and each is                    hydrogen atom or C₁₋₄ alkyl group,                    or a pharmaceutically acceptable salt thereof.

(9) The 4-oxoquinoline compound of the above-mentioned (5), wherein

-   -   R³² is a hydrogen atom, a cyano group, a halogen atom, a C₁₋₁₀        alkyl group optionally substituted by 1 to 3 substituents        selected from halogen atom and the following group B        -   wherein group B is a group consisting of C₃₋₁₀ carbon ring            group optionally substituted by 1 to 5 substituents selected            from the above-mentioned group A, heterocyclic group            (wherein the heterocyclic group is a saturated or            unsaturated ring containing, besides carbon atom(s), at            least one heteroatom selected from a nitrogen atom, an            oxygen atom and a sulfur atom) optionally substituted by 1            to 5 substituents selected from the above-mentioned group A,            —OR^(a4), —SR^(a4), —NR^(a4)R^(a5), —CONR^(a4)R^(a5),            —SO₂NR^(a4)R^(a5), —COR^(a6), —NR^(a4)COR^(a6), —SO₂R^(a6),            —NR^(a4)SO₂R^(a6), —COOR^(a4) and —NR^(a5)COOR^(a6)            -   wherein R^(a4) and R^(a5) are the same or different and                each is hydrogen atom, C₁₋₄ alkyl group, C₃₋₁₀ carbon                ring group optionally substituted by 1 to 5 substituents                selected from the above-mentioned group A or                heterocyclic group (as defined above) optionally                substituted by 1 to 5 substituents selected from the                above-mentioned group A, and R^(a6) is C₁₋₄ alkyl group,                C₃₋₁₀ carbon ring group optionally substituted by 1 to 5                substituents selected from the above-mentioned group A                or heterocyclic group (as defined above) optionally                substituted by 1 to 5 substituents selected from the                above-mentioned group A,        -   —OR^(a7), —SR^(a7), —NR^(a7)R^(a8), —NR^(a7)COR^(a9) or            —COOR^(a10)            -   wherein R^(a7) and R^(a8) are the same or different and                each is hydrogen atom, group B or C₁₋₁₀ alkyl group                optionally substituted by 1 to 3. substituents selected                from halogen atom and the above-mentioned group B,                R^(a9) is C₁₋₄ alkyl group, and R^(a10) is hydrogen atom                or C₁₋₄ alkyl group,                or a pharmaceutically acceptable salt thereof.

(10) The 4-oxoquinoline compound of the above-mentioned (9), wherein R³²is a hydrogen atom, —OR^(a7) or —NR^(a7)R^(a8) wherein R^(a7) and R^(a8)are the same or different and each is hydrogen atom, group B or C₁₋₁₀alkyl group optionally substituted by 1 to 3 substituents selected fromhalogen atom and the above-mentioned group B, or a pharmaceuticallyacceptable salt thereof.

(11) The 4-oxoquinoline compound of the above-mentioned (8), wherein

-   -   R³³ is a hydrogen atom, a C₁₋₀ alkyl group optionally        substituted by 1 to 3 substituents selected from halogen atom        and the following group B        -   wherein group B is a group consisting of C₃₋₁₀ carbon ring            group optionally substituted by 1 to 5 substituents selected            from the above-mentioned group A, heterocyclic group            (wherein the heterocyclic group is a saturated or            unsaturated ring containing, besides carbon atom(s), at            least one heteroatom selected from a nitrogen atom, an            oxygen atom and a sulfur atom) optionally substituted by 1            to 5 substituents selected from the above-mentioned group A,            —OR^(a4), —SR^(a4), —NR^(a4)R^(a5), —CONR^(a4)R^(a5),            —SO₂NR^(a4)R^(a5), —COR^(a6), —NR^(a4)COR^(a6), —SO₂R^(a6),            —NR^(a4)SO₂R^(a6), —COOR^(a4) and —NR^(a5)—COOR^(a6)            -   wherein R^(a4) and R^(a5) are the same or different and                each is hydrogen atom, C₁₋₄ alkyl group, C₃₋₁₀ carbon                ring group optionally substituted by 1 to 5 substituents                selected from the above-mentioned group A or                heterocyclic group (as defined above) optionally                substituted by 1 to 5 substituents selected from the                above-mentioned group A, and R^(a6) is C₁₋₄ alkyl group,                C₃₋₁₀ carbon ring group optionally substituted by 1 to 5                substituents selected from the above-mentioned group A                or heterocyclic group (as defined above) optionally                substituted by 1 to 5 substituents selected from the                above-mentioned group A,        -   —OR^(a7) or —NR^(a7)R^(a8)            -   wherein R^(a7) and R^(a8) are the same or different and                each is hydrogen atom, group B or C₁₋₁₀ alkyl group,                optionally substituted by 1 to 3 substituents selected                from halogen atom and the above-mentioned group B,                or a pharmaceutically acceptable salt thereof.

(12) The 4-oxoquinoline compound of the above-mentioned (11), wherein

-   -   R³³ is a hydrogen atom, —OR^(a7) or —NR^(a7)R^(a8)        -   wherein R^(a7) and R^(a8) are the same or different and each            is hydrogen atom, group B or C₁₋₁₀ alkyl group, optionally            substituted by 1 to 3 substituents selected from halogen            atom and the above-mentioned group B,            or a pharmaceutically acceptable salt thereof.

(13) The 4-oxoquinoline compound of any of the above-mentioned (8) to(12), wherein

-   -   R^(a7) and R^(a8) are the same or different and each is a C₁₋₁₀        alkyl group optionally substituted by 1 to 3 substituents        selected from halogen atom and the following group B wherein        group B is a group consisting of C₃₋₁₀ carbon ring group        optionally substituted by 1 to 5 substituents selected from the        above-mentioned group A, heterocyclic group (wherein the        heterocyclic group is a saturated or unsaturated ring        containing, besides carbon atom(s), at least one heteroatom        selected from a nitrogen atom, an oxygen atom and a sulfur atom)        optionally substituted by 1 to 5 substituents selected from the        above-mentioned group A, —OR^(a4), —SR^(a4), —NR^(a4)R^(a5),        —CONR^(a4)R^(a5), —SO₂NR^(a4)R^(a5), —COR^(a6),        —NR^(a4)COR^(a6), —SO₂R^(a6), —NR^(a4)SO₂R^(a6), —COOR^(a4) and        —NR^(a5)COOR^(a6)        -   wherein R^(a4) and R^(a5) are the same or different and each            is hydrogen atom, C₁₋₄ alkyl group, C₃₋₁₀ carbon ring group            optionally substituted by 1 to 5 substituents selected from            the above-mentioned group A or heterocyclic group (as            defined above) optionally substituted by 1 to 5 substituents            selected from the above-mentioned group A, and R^(a6) is            C₁₋₄ alkyl group, C₃₋₁₀ carbon ring group optionally            substituted by 1 to 5 substituents selected from the            above-mentioned group A or heterocyclic group (as defined            above) optionally substituted by 1 to 5 substituents            selected from the above-mentioned group A,            or a pharmaceutically acceptable salt thereof.

(14) The 4-oxoquinoline compound of the above-mentioned (5), wherein

-   -   R⁴ and R⁵ are the same or different and each is a substituent        selected from cyano group, phenyl group, nitro group, halogen        atom, C₁₋₄ alkyl group, halo C₁₋₄ alkyl group, halo C₁₋₄        alkyloxy group, —OR^(a1), —SR^(a1), —NR^(a1)R^(a2),        —CONR^(a1)R^(a2), —SO₂NR^(a1)R^(a2), —NR^(a1)COR^(a3),        —SO₂R^(a3), —NR^(a2)COOR^(a3) and —COOR^(a1)        -   wherein R^(a1) and R^(a2) are the same or different and each            is hydrogen atom, C₁₋₄ alkyl group or benzyl group, and            R^(a3) is C₁₋₄ alkyl group,            or a pharmaceutically acceptable salt thereof.

(15) The 4-oxoquinoline compound of the above-mentioned (14), wherein

-   -   R⁴ is a phenyl group, a halogen atom, a C₁₋₄ alkyl group, a halo        C₁₋₄ alkyloxy group, —OR^(a1), —NR^(a1)R^(a2), —CONR^(a1)R^(a2),        —SO₂NR^(a1)R^(a2), —NR^(a1)COR^(a3), —SO₂R^(a3),        —NR^(a1)SO₂R^(a3) or —COO^(a1)        -   wherein R^(a1) and R^(a2) are the same or different and each            is hydrogen atom, C₁₋₄ alkyl group or benzyl group, and            R^(a3) is C₁₋₄ alkyl group,            or a pharmaceutically acceptable salt thereof.

(16) The 4-oxoquinoline compound of the above-mentioned (15), wherein R⁴is a halogen atom,

or a pharmaceutically acceptable salt thereof.

(17) The 4-oxoquinoline compound of the above-mentioned (5), wherein

-   -   R⁵ is a hydrogen atom, a cyano group, a phenyl group, a nitro        group, a halogen atom, a C₁₋₄ alkyl group, a halo C₁₋₄ alkyl        group, —OR^(a1), —SR^(a1), —NR^(a1)R^(a2), —CONR^(a1)R^(a2),        —SO₂NR^(a1)R^(a2) or —NR^(a1)COR^(a3)        -   wherein R^(a1) and R^(a2) are the same or different and each            is hydrogen atom, C₁₋₄ alkyl group or benzyl group, and            R^(a3) is C₁₋₄ alkyl group,            or a pharmaceutically acceptable salt thereof.

(18) The 4-oxoquinoline compound of the above-mentioned (5), wherein R⁶is a halogen atom,

or a pharmaceutically acceptable salt thereof.

(19) The 4-oxoquinoline compound of the above-mentioned (5), wherein mis 0 or 1,

or a pharmaceutically acceptable salt thereof.

(20) The 4-oxoquinoline compound of the above-mentioned (5), wherein

-   -   R¹ is a C₃₋₁₀ carbon ring group optionally substituted by 1 to 5        substituents selected from the following group A        -   wherein group A is a group consisting of cyano group, phenyl            group, nitro group, halogen atom, C₁₋₄ alkyl group, halo            C₁₋₄ alkyl group, halo C₁₋₄ alkyloxy group, —OR^(a1),            —SR^(a1), —NR^(a1)R^(a2), —CONR^(a1)R^(a2),            —SO₂NR^(a1)R^(a2), —COR^(a3), —NR^(a1)COR^(a3), —SO₂R^(a3),            —NR^(a1)SO₂R^(a3), —COOR^(a1) and —NR^(a2)COOR^(a3)            -   wherein R^(a1) and R^(a2) are the same or different and                each is hydrogen atom, C₁₋₄ alkyl group or benzyl group                and R³ is C₁₋₄ alkyl group,        -   a substituent selected from —NR^(a4)R^(a5),            —NR^(a4)COR^(a6), —NR^(a4)SO₂R^(a6) and —NR^(a5)COOR^(a6)            -   wherein R^(a4) and R^(a5) are the same or different and                each is hydrogen atom, C₁₋₄ alkyl group, C₃₋₁₀ carbon                ring group optionally substituted by 1 to 5 substituents                selected from the above-mentioned group A or                heterocyclic groups (wherein the heterocyclic group is a                saturated or unsaturated ring containing, besides carbon                atom(s), at least one heteroatom selected from a                nitrogen atom, an oxygen atom and a sulfur atom)                optionally substituted by 1 to 5 substituents selected                from the above-mentioned group A, and R^(a6) is C₁₋₄                alkyl group, C₃₋₁₀ carbon ring group optionally                substituted by 1 to 5 substituents selected from the                above-mentioned group A or heterocyclic group (as                defined above) optionally substituted by 1 to 5                substituents selected from the above-mentioned group A,                or        -   a C₁₋₁₀ alkyl group optionally substituted by 1 to 3            substituents selected from halogen atom and group B            -   wherein group B is a group consisting of C₃₋₁₀ carbon                ring group optionally substituted by 1 to 5 substituents                selected from the above-mentioned group A, heterocyclic                group (as defined above) optionally substituted by 1 to                5 substituents selected from the above-mentioned group                A, —OR^(a4), —SR^(a4), —NR^(a4)R^(a5), —CONR^(a4)R^(a5),                —SO₂NR^(a4)R^(a5), —COR^(a6), —NR^(a4)COR^(a6),                —SO₂R^(a6), —NR^(a4)SO₂R^(a6), —COOR^(a4) and                —NR^(a5)COOR^(a6) (wherein R^(a4), R^(a5), R^(a6) and                group A are as defined above),                or a pharmaceutically acceptable salt thereof.

(21) The 4-oxoquinoline compound of the above-mentioned (20), wherein

-   -   R¹ is a C₁₋₁₀ alkyl group optionally substituted by 1 to 3        substituents selected from halogen atom and group B        -   wherein group B is a group consisting of C₃₋₁₀ carbon ring            group optionally substituted by 1 to 5 substituents selected            from the above-mentioned group A, heterocyclic group (as            defined above) optionally substituted by 1 to 5 substituents            selected from the above-mentioned group A, —OR^(a4),            —SR^(a4), —NR^(a4)R^(a5), —CONR^(a4)R^(a5),            —SO₂NR^(a4)R^(a5), —COR^(a6), —NR^(a4)COR^(a6), —SO₂R^(a6),            —NR^(a4)SO₂R^(a6), —COOR^(a4) and —NR^(a5)COOR^(a6)            -   wherein R^(a4) and R^(a5) are the same or different and                each is hydrogen atom, C₁₋₄ alkyl group, C₃₋₁₀ carbon                ring group optionally substituted by 1 to 5 substituents                selected from the above-mentioned group A or                heterocyclic group (as defined above) optionally                substituted by 1 to 5 substituents selected from the                above-mentioned group A, and R^(a6) is C₁₋₄ alkyl group,                C₃₋₁₀ carbon ring group optionally substituted by 1 to 5                substituents selected from the above-mentioned group A                or heterocyclic group (as defined above) optionally                substituted by 1 to 5 substituents selected from the                above-mentioned group A,                or a pharmaceutically acceptable salt thereof.

(22) The 4-oxoquinoline compound of the above-mentioned 5, which isselected from the group consisting of the following compounds:

-   6-(2,3-Dichlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-1),-   6-(2,3-Dichlorobenzyl)-8-fluoro-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-2),-   6-(2,3-Dichlorobenzyl)-1-(2-methanesulfonylaminoethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-3),-   6-(2,3-Dichlorobenzyl)-1-(2-imidazol-1-ylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-4),-   6-(2,3-Dichlorobenzyl)-1-dimethylcarbamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example -1-5),-   6-(2,3-Dichlorobenzyl)-1-methylcarbamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-6),-   1-Carbamoylmethyl-6-(2,3-Dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-7),-   6-(2,3-Dichlorobenzyl)-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-8),-   6-(2,3-Dichlorobenzyl)-4-oxo-1-sulfamoylmethyl-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-9),-   1-(2-Carboxyethyl)-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-10),-   1-(2-Hydroxyethyl)-6-naphthalen-1-ylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-11),-   6-(2,3-Dichlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid methyl ester (Example 1-12),-   1-(2-Carbamoylethyl)-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-13),-   6-(2,3-Dichlorobenzyl)-4-oxo-1-(2-oxopropyl)-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-14),-   1-Benzyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-15),-   6-(2,3-Dichlorobenzyl)-4-oxo-1-phenethyl-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-16),-   6-(2,3-Dichlorobenzyl)-1-(3-phenylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-17),-   6-(2,3-Dichlorobenzyl)-1-isobutyl-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-18),-   6-(2,3-Dichlorobenzyl)-1-(4-phenylbutyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-19),-   1-Biphenyl-2-ylmethyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-20),-   6-(2,3-Dichlorobenzyl)-1-(4-hydroxybutyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-21),-   1-Benzo[b]thiophen-2-ylmethyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-22),-   6-(2,3-dichlorobenzyl)-1-(3,4-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-23),-   6-(2,3-Dichlorobenzyl)-1-(2-dimethylaminoethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-24),-   6-(2,3-Dichlorobenzyl)-1-(3-hydroxypropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-25),-   6-(2,3-Dichlorobenzyl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-26),-   6-(2,3-Dichlorobenzyl)-1-(2,2,2-trifluoroethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-27),-   1-Carboxymethyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-28),-   6-(2,3-Dichlorobenzyl)-1-[2-(4-methylthiazol-5-yl)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-29),-   6-(2,3-Dichlorobenzyl)-1-(2-hydroxypropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-30),-   6-(2,3-Dichlorobenzyl)-1-(2-methylsulfanylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-32),-   6-(2-Chloro-6-fluorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-33),-   6-(2,3-Dichlorobenzyl)-1-(5-hydroxypentyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-34),-   6-(2,3-dichlorobenzyl)-1-(2-morpholin-4-ylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-35),-   6-(2,3-Dichlorobenzyl)-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-36),-   6-(2,3-Dichlorobenzyl)-1-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-37),-   6-(2,3-Dichlorobenzyl)-4-oxo-1-propyl-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-38),-   1-Butyl-6-(2,3-Dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-39),-   1-Cyclopentylmethyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-40),-   6-(2,3-Dichlorobenzyl)-1-(2-methanesulfonylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-41),-   1-Cyclohexylmethyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-42),-   6-(2,3-Dichlorobenzyl)-1-(2-hydroxy-2-phenylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-43),-   6-(2,3-Dichlorobenzyl)-1-(2-fluoroethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-44),-   6-(2,3-Dichlorobenzyl)-4-oxo-1-(2-pyridin-2-ylethyl)-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-45),-   1-(2-Aminoethyl)-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-46),-   6-(2,3-Dichlorobenzyl)-1-(2-hydroxy-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-47),-   1-(2-Acetylaminoethyl)-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-48),-   6-(2,3-Dichlorobenzyl)-1-(2-ethoxycarbonylaminoethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-49),-   6-(2,3-Difluorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-50),-   6-(2-Chloro-4-fluorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-51),-   6-(2-Chlorobenzyl)-4-oxo-1-phenethyl-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-65),-   6-(2-Chloro-3-fluorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-66),-   6-(2,3-Dichlorobenzyl)-1-methylsulfanylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-68),-   6-(2,3-Dichlorobenzyl)-1-methanesulfonylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-69),-   1-tert-Butylsulfamoylmethyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-70),-   6-(2,3-Dichlorobenzyl)-1-methylsulfamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-71),-   6-(2,3-Dichlorobenzyl)-1-dimethylsulfamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-72),-   6-(2-Chloro-3,6-difluorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-73),-   6-(2,3-Dichlorobenzyl)-1-(2,3-Dihydroxypropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-74),-   6-(2-Chloro-6-fluorobenzyl)-1-sulfamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-75),-   6-(2-Chloro-6-fluorobenzyl)-1-methylsulfamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-76),-   6-(2-Chloro-6-fluorobenzyl)-1-dimethylsulfamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-77),-   6-(2-Chloro-3-methylbenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-79),-   6-(2-Bromobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-80),-   6-(2-Chloro-3-methoxybenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-82),-   1-(2-Hydroxyethyl)-6-(2-methanesulfonylbenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-85),-   6-Biphenyl-2-ylmethyl-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-86),-   6-(2-Chlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-87),-   6-(2-Chloro-5-methylsulfanylbenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-92)-   1-(2-Hydroxyethyl)-4-oxo-6-(2-trifluoromethyloxybenzyl)-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-93),-   6-(2-Chloro-5-methylbenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-97),-   6-(3-Chloro-2-fluorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-99),-   6-(3-Chloro-2,6-difluorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-100),-   6-(2,3-Dichlorobenzyl)-1-(2-hydroxyethyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-101),-   1-Cyclopropyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 1-102),-   1-Amino-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 2-1),-   6-(2,3-Dichlorobenzyl)-1-methoxycarbonylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 2-2),-   1-Acetylamino-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 2-3),-   6-(2,3-Dichlorobenzyl)-1-methanesulfonylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 2-4),-   6-(2,3-Dichlorobenzyl)-1-(N-methanesulfonyl-N-methylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 2-5),-   6-(2,3-Dichlorobenzyl)-1-dimethylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 2-6),-   6-(2,3-Dichlorobenzyl)-1-methylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 2-7),-   6-(2,3-Dichlorobenzyl)-1-ethylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 2-8),-   6-(2,3-Dichlorobenzyl)-1-(2-hydroxyethyl)-5-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-1),-   6-(3-Chloro-2-methylbenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-2),-   6-(3-Chloro-2-methoxybenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-3),-   6-(3-Chloro-2-fluorobenzyl)-1-(2-hydroxyethyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-4),-   6-(2,3-Dichlorobenzyl)-5-hydroxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-5),-   6-(2,3-Dichlorobenzyl)-7-hydroxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-6),-   1-(2-Hydroxyethyl)-6-(2-methylaminobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-7),-   6-(2-Dimethylaminobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-8),-   6-(2,3-Dichlorobenzyl)-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-9),-   6-(2,3-Dichlorobenzyl)-1-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-10),-   1-Cyclobutyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-12),-   1-Cyclopentyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-13),-   6-(2,3-Dichlorobenzyl)-1-(2-hydroxyethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-14),-   6-(2-Dimethylsulfamoylbenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-16),-   6-(3-Chloro-2,4-difluorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-17),-   6-(2-Carboxybenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-18),-   1-(2-Hydroxyethyl)-6-(2-methylsulfamoylbenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-19),-   6-(2,3-Dichlorobenzyl)-7-ethoxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-20),-   7-Chloro-6-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-21),-   6-(2,3-Dichlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-7-trifluoromethyl-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-22),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-(2-hydroxy-1-methylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-23),-   (R)-6-(3-Chloro-2-fluorobenzyl)-1-(2-hydroxy-1-methylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-24),-   6-(3-Chloro-2-fluorobenzyl)-1-(2-hydroxyethyl)-4-oxo-8-trifluoromethyl-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-25),-   6-(3-Chloro-2-fluorobenzyl)-1-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-26),-   7-Cyano-6-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-27),-   6-(2-Ethylmethylaminobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-28),-   6-[2-(N-Methyl-N-propylamino)benzyl]-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-29),-   6-[2-(N-Benzyl-N-methylamino)benzyl]-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-30),-   6-[2-(N-Methanesulfonyl-N-methylamino)benzyl]-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-31),-   6-[2-(N-Isopropyl-N-methylamino)benzyl]-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-32),-   1-tert-Butyl-6-(3-Chloro-2-fluorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-33),-   6-(3-Chloro-2-fluorobenzyl)-1-(2-hydroxyethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-34),-   8-Amino-6-(3-chloro-2-fluorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-35),-   7-Carboxy-6-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-36),-   6-(3-Chloro-2,6-difluorobenzyl)-1-(2-hydroxyethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-37),-   6-(3-Chloro-2-fluorobenzyl)-8-dimethylamino-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-38),-   8-Acetylamino-6-(3-chloro-2-fluorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-39),-   5-Cyano-6-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-40),-   6-[2-(N-Acetyl-N-methylamino)benzyl]-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-41),-   6-(2-Diethylaminobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-42),-   6-(3-Chloro-2-fluorobenzyl)-1-(1,1-dimethyl-2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-43),-   6-(3-Chloro-2-fluorobenzyl)-7-ethoxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-44),-   6-(3-Chloro-2-fluorobenzyl)-7,8-dimethoxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-45),-   6-(3-Chloro-2-fluorobenzyl)-8-ethoxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-47),-   6-(3-Chloro-2-fluorobenzyl)-1-(2-hydroxyethyl)-8-methylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-48),-   6-(3-Chloro-2-fluorobenzyl)-1-(2-hydroxyethyl)-4-oxo-7-propyloxy-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-49),-   6-(3-Chloro-2-fluorobenzyl)-7-(dimethylaminomethyleneamino)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-50),-   6-(3-Chloro-2-fluorobenzyl)-1-(2-hydroxyethyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid methyl ester (Example 3-51),-   6-(3-Chloro-2-fluorobenzyl)-1-(2-hydroxyethyl)-4-oxo-8-phenoxy-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-52),-   6-(3-Chloro-2-fluorobenzyl)-1-(2-hydroxyethyl)-7-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-53),-   6-(3-Chloro-2-fluorobenzyl)-1-(2-hydroxyethyl)-4-oxo-8-propylamino-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-54),-   6-(3-Chloro-2-fluorobenzyl)-8-ethylamino-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-55),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-(2-hydroxy-1-methylethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-56),-   (S)-6-(3-Chloro-2,6-difluorobenzyl)-1-(2-hydroxy-1-methylethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example-3-57),-   6-(3-Chloro-2-fluorobenzyl)-1-(2-hydroxyethyl)-4-oxo-8-propyloxy-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-58),-   6-(3-Chloro-2-fluorobenzyl)-1-(2-hydroxyethyl)-8-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-59),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-[1-(hydroxymethyl)propyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-60),-   (S)-6-(3-Chloro-2-fluorobenzyl)-7-ethoxy-1-(2-hydroxy-1-methylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-61),-   6-(3-Chloro-2-fluorobenzyl)-7-dimethylamino-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-62),-   6-(3-Chloro-2-fluorobenzyl)-7-cyclohexylmethoxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-63),-   6-(3-Chloro-2-fluorobenzyl)-8-diethylamino-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-64),-   6-(3-Chloro-2-fluorobenzyl)-7-methylamino-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-65),-   6-(3-Chloro-2-fluorobenzyl)-1-(2-hydroxyethyl)-4-oxo-7-pyrrolidin-1-yl-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-66),-   (S)-6-(3-Chloro-2-fluorobenzyl)-8-ethoxy-1-(2-hydroxy-1-methylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-67),-   (S)-6-(3-Chloro-2-fluorobenzyl)-7-ethoxy-1-[1-(hydroxymethyl)propyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-68),-   6-(3-Chloro-2-fluorobenzyl)-8-cyclohexylmethoxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-69),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-(1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-70),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-(1-hydroxymethyl-3-methylbutyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-71),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-[1-(hydroxymethyl)propyl]-7-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-72),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-[1-(hydroxymethyl)propyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-73),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-(2-hydroxy-1-methylethyl)-7-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-74),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-[2,2-dimethyl-1-(hydroxymethyl)propyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example -3-75),-   6-(3-Chloro-2-fluorobenzyl)-1-(2-hydroxyethyl)-7-(2-hydroxyethyloxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-76),-   6-(3-Chloro-2-fluorobenzyl)-1-(2-hydroxyethyl)-1-7-(3-hydroxypropyloxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-77),-   6-(3-Chloro-2-fluorobenzyl)-1-(2-hydroxyethyl)-8-(2-hydroxyethylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-78),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-[1-(hydroxymethyl)propyl]-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-79),-   (S)-6-(3-Chloro-2-fluorobenzyl)-8-dimethylamino-1-(2-hydroxy-1-methylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-80),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-(2-hydroxy-1-phenylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-81),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-[1-(hydroxymethyl)butyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-82),-   6-(3-Chloro-2-fluorobenzyl)-1-((1S,2S)-1-hydroxymethyl-2-methylbutyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-83),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-(2-hydroxy-1-methylethyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-84),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-(1-benzyl-2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 3-85),-   6-(2-Chloro-5-methanesulfonylbenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-1),-   6-(2-Ethylbenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-4),-   6-(2-Chloro-5-methylbenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-5),-   6-(2-Chloro-5-fluorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-6),-   6-(5-Bromo-2-chlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-7),-   6-(2,3-Dichlorobenzyl)-7-fluoro-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-9)-   6-(2-Chloro-5-hydroxybenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-11),-   6-(2,3-Dichlorobenzyl)-5-fluoro-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-12),-   6-(2-Ethoxybenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-13),-   6-(2-Hydroxybenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-14),-   6-(2,3-Dichlorobenzyl)-7-methyl-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-15),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-(2-hydroxy-1-methylethyl)-8-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-16),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-[1-(hydroxymethyl)propyl]-8-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-17),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-(1-cyclohexyl-2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-18),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-(1-hydroxymethyl-2-methylpropyl)-7-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-19),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-[2,2-dimethyl-1-(hydroxymethyl)propyl]-7-isopropyloxy-4-oxo-1,    4-dihydroquinoline-3-carboxylic acid (Example 4-20),-   (S)-6-(3-Chloro-2-fluorobenzyl)-8-ethoxy-1-[1-(hydroxymethyl)propyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-21),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-[2-cyclohexyl-1-(hydroxymethyl)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-22),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-(1-hydroxymethyl-3-methylbutyl)-7-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-23),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-(1-hydroxymethyl-2-methylpropyl)-8-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-24),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-(1-hydroxymethyl-3-methylbutyl)-8-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-25),-   (S)-6-(3-Chloro-2-fluorobenzyl)-[2,2-dimethyl-1-(hydroxymethyl)propyl]-8-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-26),-   6-(3-Chloro-2-fluorobenzyl)-1-((1S,2S)-1-hydroxymethyl-2-methylbutyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-27),-   6-(3-Chloro-2-fluorobenzyl)-7-ethoxy-1-((1S,2S)-1-hydroxymethyl-2-methylbutyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-28),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-[1-(hydroxymethyl)propyl]-7-methylsulfanyl-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-29),-   (S)-6-(3-Chloro-2-fluorobenzyl)-7-ethoxy-1-(1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-30),-   (S)-6-(3-Chloro-2-fluorobenzyl)-7-ethoxy-1-[2,2-dimethyl-1-(hydroxymethyl)propyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-31),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-(1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-32),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-[2,2-dimethyl-1-(hydroxymethyl)propyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-33),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-[2,2-dimethyl-1-(hydroxymethyl)propyl]-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-34),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-[1-(hydroxyethyl)butyl]-7-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-35),-   (S)-6-(3-Chloro-2-fluorobenzyl)-7-ethoxy-1-[1-(hydroxymethyl)butyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-36),-   (S)-6-(3-Chloro-2-fluorobenzyl)-8-ethoxy-1-[2,2-dimethyl-1-(hydroxymethyl)propyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-37),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-[1-(hydroxymethyl)butyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-38),-   6-(3-Chloro-2-fluorobenzyl)-1-((1S,2S)-1-hydroxymethyl-2-methylbutyl)-7-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-39),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-(1-cyclohexyl-2-hydroxyethyl)-7-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-40),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-(1-cyclohexyl-2-hydroxyethyl)-8-ethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-41),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-(1-cyclohexyl-2-hydroxyethyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-42),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-(1-cyclohexyl-2-hydroxyethyl)-7-ethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-43),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-(1-cyclohexyl-2-hydroxyethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-44),-   (S)-6-(3-Chloro-2-fluorobenzyl)-8-ethoxy-1-(1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-45),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-(1-hydroxymethyl-2-methylpropyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-46),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-[1-(hydroxymethyl)butyl]-8-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-47),-   (S)-6-(3-Chloro-2-fluorobenzyl)-8-ethoxy-1-[1-(hydroxymethyl)butyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-48),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-[1-(hydroxymethyl)butyl]-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-49),-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-(1-cyclohexyl-2-hydroxyethyl)-8-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-50) and-   (S)-6-(3-Chloro-2-fluorobenzyl)-1-[2,2-dimethyl-1-(hydroxymethyl)propyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid (Example 4-52),    or a pharmaceutically acceptable salt thereof.

(23) A pharmaceutical composition comprising a 4-oxoquinoline compoundof any of the above-mentioned (5) to (22), or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

(24) An integrase inhibitor comprising a 4-oxoquinoline compound of anyof the above-mentioned (1) to (22), or a pharmaceutically acceptablesalt thereof, as an active ingredient.

(25) An antiviral agent comprising a 4-oxoquinoline compound of any ofthe above-mentioned (5) to (22), or a pharmaceutically acceptable saltthereof, as an active ingredient.

(26) An anti-HIV agent comprising a 4-oxoquinoline compound of any ofthe above-mentioned (5) to (22), or a pharmaceutically acceptable saltthereof, as an active ingredient.

(27) An anti-HIV composition comprising a 4-oxoquinoline compound of anyof the above-mentioned (1) to (22), or a pharmaceutically acceptablesalt thereof, and other one or more kinds of anti-HIV active substanceas an active ingredient.

(28) An anti-HIV agent comprising a 4-oxoquinoline compound of any ofthe above-mentioned (1) to (22), or a pharmaceutically acceptable saltthereof, as an active ingredient, for multiple drug therapy with otheranti-HIV agent(s).

(29) Use of a 4-oxoquinoline compound of any of the above-mentioned (5)to (22) or a pharmaceutically acceptable salt thereof, for theproduction of an anti-HIV agent.

(30) Use of a 4-oxoquinoline compound of any of the above-mentioned (5)to (22) or a pharmaceutically acceptable salt thereof, for theproduction of an integrase inhibitor.

(31) Use of a 4-oxoquinoline compound of any of the above-mentioned (5)to (22) or a pharmaceutically acceptable salt thereof, for theproduction of an antiviral agent.

(32) A method for the prophylaxis or treatment of an HIV infectiousdisease, which comprises administering an effective amount of a4-oxoquinoline compound of any of the above-mentioned (5) to (22) or apharmaceutically acceptable salt thereof to a mammal.

(33) The method for the prophylaxis or treatment of an HIV infectiousdisease according to the above-mentioned (32), which further comprisesadministering an effective amount of at least one different anti-HIVactive substance to said mammal.

(34) A method for inhibiting integrase, which comprises administering aneffective amount of a 4-oxoquinoline compound of any of theabove-mentioned (5) to (22) or a pharmaceutically acceptable saltthereof to a mammal.

(35) A method for the prophylaxis or treatment of a virus infectiousdisease, which comprises administering an effective amount of a4-oxoquinoline compound of any of the above-mentioned (5) to (22) or apharmaceutically acceptable salt thereof to a mammal.

(36) An anti-HIV composition comprising a 4-oxoquinoline compound of anyof the above-mentioned (5) to (22) or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

(37) A pharmaceutical composition for inhibiting integrase, whichcomprises a 4-oxoquinoline compound of any of the above-mentioned (5) to(22) or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

(38) An antiviral composition comprising a 4-oxoquinoline compound ofany of the above-mentioned (5) to (22) or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

(39) A commercial package comprising the composition of theabove-mentioned 36 and a written matter associated therewith, thewritten matter stating that the composition can or should be used forthe prophylaxis or treatment of an HIV infectious disease.

(40) A commercial package comprising the composition of theabove-mentioned (37) and a written matter associated therewith, thewritten matter stating that the composition can or should be used forinhibiting integrase.

(41) A commercial package comprising the composition of theabove-mentioned (38) and a written matter associated therewith, thewritten matter stating that the composition can or should be used forthe prophylaxis or treatment of a viral infectious disease.

The definitions of each substituent and each moiety used in the presentspecification are as follows.

The “halogen atom” means fluorine atom, chlorine atom, bromine atom oriodine atom, preferably fluorine atom, chlorine atom or bromine atom.

As R³², R³³, R⁴, R⁵, R⁶, R^(6′), R^(6″), R^(6′″) and group A, fluorineatom and chlorine atom are particularly preferable, as R³² and R⁵,chlorine atom is more preferable, and as R³¹, R³³, R⁴, R^(6′), R^(6′″)and the halogen atom of the “C₁₋₁₀ alkyl group optionally substituted by1 to 3 substituents selected from halogen atom and group B”, fluorineatom is more preferable.

The “C₁₋₄ alkyl group” means a straight chain or branched chain alkylgroup having 1 to 4 carbon atoms, which is specifically methyl group,ethyl group, propyl group, isopropyl group, butyl group, isobutyl group,sec-butyl group or tert-butyl group.

As R², R³¹ and R^(a6), methyl group and ethyl group are preferable, asR⁴, R⁵, R⁶, R^(6′), R^(6″), R^(6′″) and group A, methyl group, ethylgroup and isopropyl group are preferable, methyl group is morepreferable, as R^(a1) and R^(a2), methyl group, ethyl group, propylgroup and isopropyl group are preferable, methyl group is morepreferable, as R^(a3), R^(a9), R^(a10), R^(a11) and group A, methylgroup is preferable, and as R^(a4) and R^(a5), methyl group, ethyl groupand tert-butyl group are preferable.

The “halo C₁₋₄ alkyl group” is “C₁₋₄ alkyl group” defined above, whichis substituted by 1 to 9, preferably 1 to 3, “halogen atom” definedabove.

Specific examples thereof include 2-fluoroethyl group, 2-chloroethylgroup, 2-bromomethyl group, 3-fluoropropyl group, 3-chloropropyl group,4-fluorobutyl group, 4-chlorobutyl group, trifluoromethyl group,2,2,2-trifluoroethyl group, 3,3,3-trifluoropropyl group,4,4,4-trifluorobutyl group, pentafluoroethyl group,2,2,2-trifluoro-1-trifluoromethyl-ethyl group and the like.

As R³¹, R⁴, R⁵, R⁶, R^(6′), R^(6″), R^(6′″) and group A, trifluoromethylgroup is preferable.

“The “C₁₋₄ alkoxy group” is an alkyloxy group wherein its alkyl moietyis “C₁₋₄ alkyl group” defined above, which is specifically exemplifiedby methoxy group, ethoxy group, propoxy group, isopropyloxy group,butoxy group, isobutyloxy group, tert-butyloxy group and the like.

It is preferably methoxy group for R³¹.

The “C₁₋₄ alkylsulfanyl group” is an alkylsulfanyl group wherein itsalkyl moiety is “C₁₋₄ alkyl group” defined above. Specific examplesthereof include methylsulfanyl group, ethylsulfanyl group,propylsulfanyl group, isopropylsulfanyl group, butylsulfanyl group,isobutylsulfanyl group, tert-butylsulfanyl group and the like.

It is preferably methylsulfanyl group for R³¹.

The “halo C₁₋₄ alkyloxy group” is a halo C₁₋₄ alkyloxy group wherein itshaloalkyl moiety is “halo C₁₋₄ alkyl group” defined above.

Specific examples thereof include 2-fluoroethyloxy group,2-chloroethyloxy group, 2-bromomethyloxy group, 3-fluoropropyloxy group,3-chloropropyloxy group, 4-fluorobutyloxy group, 4-chlorobutyloxy group,trifluoromethyloxy group, 2,2,2-trifluoroethyloxy group,3,3,3-trifluoropropyloxy group, 4,4,4-trifluorobutyloxy group,pentafluoroethyloxy group, 2,2,2-trifluoro-1-trifluoromethylethyloxygroup and the like.

It is preferably trifluoromethyloxy group for R³¹, R⁴, R⁵, R⁶, R^(6′),R^(6″), R^(6′″) and group A.

The “C₃₋₁₀ carbon ring group” is a saturated or unsaturated cyclichydrocarbon group having 3 to 10 carbon atoms, which is specificallyexemplified by aryl group, cycloalkyl group, cycloalkenyl group or afused ring thereof.

Specific examples of the “aryl group” include phenyl group, naphthylgroup, pentalenyl group, azulenyl group and the like, preferably phenylgroup and naphthyl group, particularly preferably phenyl group.

Specific examples of the “cycloalkyl group” include cyclopropyl group,cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptylgroup, cyclooctyl group, adamantyl group, norbornanyl group and thelike, preferably cyclopropyl group, cyclobutyl group, cyclopentyl groupand cyclohexyl group.

The “cycloalkenyl group” contains at least one, preferably 1 or 2 doublebonds, and is specifically exemplified by cyclopropenyl group,cyclobutenyl group, cyclopentenyl group, cyclopentadienyl group,cyclohexenyl group, cyclohexadienyl group (2,4-cyclohexadien-1-yl group,2,5-cyclohexadien-1-yl group and the like), cycloheptenyl group andcyclooctenyl group and the like.

Specific examples of the fused ring of these “aryl group”, “cycloalkylgroup” and “cycloalkenyl group” include indenyl group, indanyl group,1,4-dihydronaphthyl group, 1,2,3,4-tetrahydronaphthyl group(1,2,3,4-tetrahydro-2-naphthyl group, 5,6,7,8-tetrahydro-2-naphthylgroup and the like), perhydronaphthyl group and the like. Preferably, itis a fused ring of phenyl group and a different ring, which isexemplified by indenyl group, indanyl group, 1,4-dihydronaphthyl group,1,2,3,4-tetrahydronaphthyl group and the like, and indanyl group isparticularly preferable.

The “C₃₋₁₀ carbon ring group optionally substituted by 1 to 5substituents selected from group A” is a “C₃₋₁₀ carbon ring group”defined above, which is optionally substituted by 1 to 5, preferably 1to 3, substituents selected from the following group A, and includesnon-substituted “C₃₋₁₀ carbon ring group”.

The “group A” is a group constituting of cyano group, phenyl group,nitro group, “halogen atom” defined above, “C₁₋₄ alkyl group” definedabove, “halo C₁₋₄ alkyl group” defined above, “halo C₁₋₄ alkyloxy group”defined above, —OR^(a1), —SR^(a1), —NR^(a1)R^(a2), —CONR^(a1)R^(a2),—SO₂NR^(a1)R^(a2), —COR^(a3), —NR^(a1)COR^(a3), —SO₂R^(a3),—NR^(a1)SO₂R^(a3), —COOR^(a1) and —NR^(a2)COOR^(a3), wherein R^(a1) andR^(a2) are the same or different and each is hydrogen atom, “C₁₋₄ alkylgroup” defined above or benzyl group, and R^(a3) is “C₁₋₄ alkyl group”defined above.

Specific examples of “—OR^(a1)” include hydroxy group, methoxy group,ethoxy group, propoxy group, isopropyloxy group, tert-butoxy group andthe like,

specific examples of “—SR^(a1)” include mercapto group, methylsulfanylgroup, ethylsulfanyl group, propylsulfanyl group, isopropylsulfanylgroup, tert-butylsulfanyl group and the like,

specific examples of “—NR^(a1)R^(a2)” include amino group, methylaminogroup, ethylamino group, propylamino group, isopropylamino group,tert-butylamino group, dimethylamino group, diethylamino group,N-ethyl-N-methylamino group, N-methyl-N-propylamino group,N-isopropyl-N-methylamino group, N-benzyl-N-methylamino group and thelike,

specific examples of “—CONR^(a1)R^(a2)” include carbamoyl group,methylaminocarbonyl group, ethylaminocarbonyl group, propylaminocarbonylgroup, isopropylaminocarbonyl group, tert-butylaminocarbonyl group,dimethylaminocarbonyl group, diethylaminocarbonyl group,N-methyl-N-ethylaminocarbonyl group and the like,

specific examples of “—SO₂NR^(a1)R^(a2) include sulfamoyl group,methylaminosulfonyl group, ethylaminosulfonyl group, propylaminosulfonylgroup, isopropylaminosulfonyl group, tert-butylaminosulfonyl group,dimethylaminosulfonyl group, diethylaminosulfonyl group,N-methyl-N-ethylaminosulfonyl group and the like,

specific examples of “—COR^(a3)” include acetyl group, propionyl group,butyryl group, isobutyryl group, pivaloyl group and the like,

specific examples of “—NR^(a1)COR^(a3)” include acetylamino group,propionylamino group, butyrylamino group, isobutyrylamino group,pivaloylamino group, N-acetyl-N-methylamino group and the like,

specific examples of “—SO₂R^(a3)” include methylsulfonyl group,ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group,tert-butylsulfonyl group and the like,

specific examples of “—NR^(a1)SO₂R^(a3)” include methylsulfonylaminogroup, ethylsulfonylamino group, propylsulfonylamino group,isopropylsulfonylamino group, tert-butylsulfonylamino group,N-methyl-N-(methylsulfonyl)amino group and the like,

specific examples of “—COOR^(a1)” include carboxyl group,methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group,isopropyloxycarbonyl group, tert-butoxycarbonyl group and the like, and

specific examples of “—NR^(a2)COOR^(a3)” include methoxycarbonylaminogroup, ethoxycarbonylamino group, propoxycarbonylamino group,isopropyloxycarbonylamino group, tert-butoxycarbonylamino group and thelike.

As group A, cyano group, phenyl group, nitro group, fluorine atom,chlorine atom, bromine atom, methyl group, ethyl group, isopropyl group,trifluoromethyl group, trifluoromethyloxy group, hydroxy group, methoxygroup, ethoxy group, propoxy group, methylsulfanyl group, amino group,methylamino group, ethylamino group, isopropylamino group, dimethylaminogroup, diethylamino group, N-ethyl-N-methylamino group,N-methyl-N-propylamino group, N-isopropyl-N-methylamino group,N-benzyl-N-methylamino group, carbamoyl group, methylaminocarbonylgroup, dimethylaminocarbonyl group, sulfamoyl group, methylaminosulfonylgroup, dimethylaminosulfonyl group, acetyl group, acetylamino group,N-acetyl-N-methylamino group, methylsulfonyl group, methylsulfonylaminogroup, N-methyl-N-(methylsulfonyl)amino group, carboxyl group,methoxycarbonyl group, carboxyamino group and methoxycarbonylamino groupare preferable.

As group A, cyano group, phenyl group, nitro group, fluorine atom,chlorine atom, bromine atom, methyl group, trifluoromethyl group,trifluoromethyloxy group, hydroxy group, methoxy group, ethoxy group,methylsulfanyl group, amino group, methylamino group, dimethylaminogroup, diethylamino group, N-ethyl-N-methylamino group,N-methyl-N-propylamino group, N-isopropyl-N-methylamino group,N-benzyl-N-methylamino group, dimethylaminocarbonyl group,methylaminosulfonyl group, dimethylaminosulfonyl group, acetylaminogroup, N-acetyl-N-methylamino group, methylsulfonyl group,N-methyl-N-(methylsulfonyl)amino group and carboxyl group areparticularly preferable, and fluorine atom and chlorine atom are morepreferable.

The number of substituents is preferably 1 to 3, and when “C₃₋₁₀ carbonring group” is phenyl group, ring Cy is preferably monosubstituted atthe 2-position, monosubstituted at the 3-position, disubstituted at the2,3-positions, disubstituted at the 2,4-positions, disubstituted at the2,5-positions, disubstituted at the 2,6-positions, trisubstituted at the2,3,4-positions, trisubstituted at the 2,3,5-positions, trisubstitutedat the 2,3,6-positions, particularly preferably disubstituted at the2,3-positions.

Specific examples of the “C₃₋₁₀ carbon ring group optionally substitutedby 1 to 5 substituents selected from group A” include phenyl group,naphthyl group, 2-fluorophenyl group, 2-chlorophenyl group,2-bromophenyl group, 3-fluorophenyl group, 3-chlorophenyl group,3-bromophenyl group, 4-fluorophenyl group, 2-nitrophenyl group,3-nitrophenyl group, 2-cyanophenyl group, 3-cyanophenyl group,2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group,2-ethylphenyl group, 3-ethylphenyl group, 2-isopropylphenyl group,3-isopropylphenyl group, 2-trifluoromethylphenyl group,3-trifluoromethylphenyl group, 2-hydroxyphenyl group, 3-hydroxyphenylgroup, 4-hydroxyphenyl group, 2-methoxyphenyl group, 3-methoxyphenylgroup, 2-ethoxyphenyl group, 3-ethoxyphenyl group, 2-propoxyphenylgroup, 3-propoxyphenyl group, 2-(trifluoromethyl)phenyl group,3-(trifluoromethyl)phenyl group, 2-(trifluoromethyloxy)phenyl group,3-(trifluoromethyloxy)phenyl group, 2-methylsulfamoylphenyl group,3-methylsulfamoylphenyl group, 2-aminophenyl group, 3-aminophenyl group,2-(methylamino)phenyl group, 3-(methylamino)phenyl group,2-(dimethylamino)phenyl group, 3-(dimethylamino)phenyl group,2-(acetylamino)phenyl group, 3-(acetylamino)phenyl group, 2-biphenylgroup, 3-biphenyl group, 2-(methylsulfonyl)phenyl group,3-(methylsulfonyl)phenyl group, 2-sulfamoylphenyl group,3-sulfamoylphenyl group, 2-(methylaminosulfonyl)phenyl group,3-(methylaminosulfonyl)phenyl group, 2-(dimethylaminosulfonyl)phenylgroup, 3-(dimethylaminosulfonyl)phenyl group, 2-(dimethylsulfonyl)phenylgroup, 2-(methylsulfonylamino)phenyl group,3-(methylsulfonylamino)phenyl group, 2-carbamoylphenyl group,3-carbamoylphenyl group, 2-(methylcarbamoyl)phenyl group,3-(methylcarbamoyl)phenyl group, 2-(dimethylcarbamoyl)phenyl group,3-(dimethylcarbamoyl)phenyl group, 2,3-difluorophenyl group,2,3-dichlorophenyl group, 2,3-dibromophenyl group, 2,4-difluorophenylgroup, 2,4-dichlorophenyl group, 2,5-dichlorophenyl group,2,6-dichlorophenyl group, 2-chloro-3-fluorophenyl group,2-chloro-4-fluorophenyl group, 2-chloro-5-fluorophenyl group,2-chloro-6-fluorophenyl group, 3-chloro-2-fluorophenyl group,5-chloro-2-fluorophenyl group, 5-bromo-2-chlorophenyl group,2-chloro-5-nitrophenyl group, 2-chloro-3-methylphenyl group,2-chloro-5-methylphenyl group, 2-chloro-3-(trifluoromethyl)phenyl group,2-chloro-5-(trifluoromethyl)phenyl group, 2-chloro-3-hydroxyphenylgroup, 2-chloro-5-hydroxyphenyl group, 2-chloro-3-methoxyphenyl group,2-chloro-5-methoxyphenyl group, 2-chloro-3-methylsulfamoylphenyl group,2-chloro-5-methylsulfamoylphenyl group, 2-chloro-3-aminophenyl group,2-chloro-5-aminophenyl group, 2-chloro-3-(methylamino)phenyl group,2-chloro-5-(methylamino)phenyl group, 2-chloro-3-(dimethylamino)phenylgroup, 2-chloro-5-(dimethylamino)phenyl group,2-chloro-3-(acetylamino)phenyl group, 2-chloro-5-(acetylamino)phenylgroup, 2-chloro-3-(methylsulfonyl)phenyl group,2-chloro-5-(methylsulfonyl)phenyl group,2-chloro-3-(methylsulfonylamino)phenyl group,2-chloro-5-(methylsulfonylamino)phenyl group, 2,3,4-trifluorophenylgroup, 2-chloro-3,4-difluorophenyl group, 2-chloro-3,5-difluorophenylgroup, 2-chloro-3,6-difluorophenyl group, 2-chloro-4,5-difluorophenylgroup, 2-chloro-4,6-difluorophenyl group, 3-chloro-2,4-difluorophenylgroup, 3-chloro-2,5-difluorophenyl group, 3-chloro-2,6-difluorophenylgroup, 2,3-dichloro-4-fluorophenyl group,3-chloro-2-fluoro-5-trifluoromethylphenyl group,2-chloro-3,5,6-trifluorophenyl group, 3-chloro-2,4,5-trifluorophenylgroup, 3-chloro-2,4,6-trifluorophenyl group,2,3-dichloro-4,5,6-trifluorophenyl group,3,5-dichloro-3,4,6-trifluorophenyl group,2,6-dichloro-3,4,5-trifluorophenyl group, perfluorophenyl group,cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexylgroup, 2-hydroxycyclopropyl group, 3-hydroxycyclobutyl group,3-hydroxycyclopentyl group, 2-hydroxycyclohexyl group,3-hydroxycyclohexyl group, 4-hydroxycyclohexyl group, 4-indanyl groupand 1H-inden-4-yl group.

The ring Cy is preferably phenyl group, naphthyl group, 2-chlorophenylgroup, 3-chlorophenyl group, 2-bromophenyl group, 3-bromophenyl group,2-ethylphenyl group, 3-ethylphenyl group, 2-hydroxyphenyl group,2-ethoxyphenyl group, 3-(trifluoromethyloxy)phenyl group,3-(methylsulfonyl)phenyl group, 2,3-difluorophenyl group,2,3-dichlorophenyl group, 2-chloro-3-fluorophenyl group,2-chloro-4-fluorophenyl group, 2-chloro-5-fluorophenyl group,2-chloro-6-fluorophenyl group, 3-chloro-2-fluorophenyl group,5-bromo-2-chlorophenyl group, 2-chloro-5-methylphenyl group,2-chloro-5-hydroxyphenyl group, 2-chloro-5-(methylsulfonyl)phenyl group,2-chloro-3,6-difluorophenyl group, 3-chloro-2,4-difluorophenyl group,3-chloro-2,6-difluorophenyl group, 2-chloro-3-methylphenyl group,3-chloro-2-methylphenyl group, 2-chloro-3-methoxyphenyl group,3-chloro-2-methoxyphenyl group, 3-nitrophenyl group, 3-cyanophenylgroup, 4-methylphenyl group, 3-trifluoromethylphenyl group,2-(trifluoromethyloxy)phenyl group, 3-hydroxyphenyl group,3-ethoxyphenyl group, 3-aminophenyl group, 2-(methylamino)phenyl group,2-(dimethylamino)phenyl group, 2-(diethylamino)phenyl group,2-(N-ethyl-N-methylamino)phenyl group,2-(N-isopropyl-N-methylamino)phenyl group,2-(N-benzyl-N-methylamino)phenyl group, 2-(N-acetyl-N-methylamino)phenylgroup, 2-(N-methyl-N-methylsulfonylamino)phenyl group,3-(methylamino)phenyl group, 2-carboxyphenyl group,3-(dimethylaminocarbonyl)phenyl group, 3-(acetylamino)phenyl group,2-biphenyl group, 2-(methylsulfonyl)phenyl group,2-chloro-5-methylsulfanylphenyl group, 2-chloro-5-methylphenyl group,2-(methylaminosulfonyl)phenyl group, 2-(dimethylaminosulfonyl)phenylgroup or 3-(dimethylaminosulfonyl)phenyl group, particularly preferably2-chlorophenyl group, 2-bromophenyl group, 2-ethylphenyl group,2-hydroxyphenyl group, 2-ethoxyphenyl group, 2,3-difluorophenyl group,2,3-dichlorophenyl group, 2-chloro-3-fluorophenyl group,3-chloro-2-fluorophenyl group, 2-chloro-4-fluorophenyl group,2-chloro-5-fluorophenyl group, 2-chloro-6-fluorophenyl group,5-bromo-2-chlorophenyl group, 2-chloro-5-hydroxyphenyl group,2-chloro-5-(methylsulfonyl)phenyl group, 2-chloro-3,6-difluorophenylgroup, 3-chloro-2,6-difluorophenyl group, 2-chloro-3-methylphenyl group,2-chloro-3-methoxyphenyl group, 2-trifluoromethylphenyl group,2-(methylsulfonyl)phenyl group, 2-chloro-5-methylsulfanylphenyl group,2-chloro-5-methylphenyl group or 2-(dimethylaminosulfonyl)phenyl group,and more preferably 2,3-dichlorophenyl group, 2,3-difluorophenyl group,2-chloro-3-fluorophenyl group or 3-chloro-2-fluorophenyl group.

R¹ and group B are preferably phenyl group, 3,4-dichlorophenyl group,2-biphenyl group, cyclopropyl group, 2-hydroxycyclopropyl group,cyclobutyl group, 2-hydroxycyclobutyl group, 3-hydroxycyclobutyl group,cyclopentyl group, 2-hydroxycyclopentyl group, 3-hydroxycyclopentylgroup, cyclohexyl group, 2-hydroxycyclohexyl group, 3-hydroxycyclohexylgroup and 4-hydroxycyclohexyl group, particularly preferably phenylgroup, 3,4-dichlorophenyl group, 2-biphenyl group, cyclopropyl group,cyclobutyl group, cyclopentyl group and cyclohexyl group.

As R³², R³³, R¹ and group B, phenyl group and cyclohexyl group arepreferable.

The “heterocyclic group” means a saturated or unsaturated (inclusive ofpartially unsaturated and completely unsaturated ones) monocyclic 5- or6-membered heterocycle containing, besides carbon atom, at least one,preferably 1 to 4, heteroatoms selected from nitrogen atom, oxygen atomand sulfur atom, a fused ring of these heterocycles, or a fused ring ofC₃₋₁₀ carbon ring and heterocycle, wherein the carbon ring is selectedfrom benzene, cyclopentane and cyclohexane.

Examples of the “saturated monocyclic heterocyclic group” includepyrrolidinyl group, tetrahydrofuryl group, tetrahydrothienyl group,imidazolidinyl group, pyrazolidinyl group, 1,3-dioxolanyl group,1,3-oxathiolanyl group, oxazolidinyl group, thiazolidinyl group,piperidinyl group, piperazinyl group, tetrahydropyranyl group,tetrahydrothiopyranyl group, dioxanyl group, morpholinyl group,thiomorpholinyl group, 2-oxopyrrolidinyl group, 2-oxopiperidinyl group,4-oxopiperidinyl group, 2,6-dioxopiperidinyl group and the like.Preferably, it is pyrrolidinyl group, piperidinyl group or morpholinylgroup.

Examples of the “unsaturated monocyclic heterocyclic group” includepyrrolyl group, furyl group, thienyl group, imidazolyl group,1,2-dihydro-2-oxoimidazolyl group, pyrazolyl group, diazolyl group,oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group,1,2,4-triazolyl group, 1,2,3-triazolyl group, tetrazolyl group,1,3,4-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,3,4-thiadiazolylgroup, 1,2,4-thiadiazolyl group, furazanyl group, pyridyl group,pyrimidinyl group, 3,4-dihydro-4-oxopyrimidinyl group, pyridazinylgroup, pyrazinyl group, 1,3,5-triazinyl group, imidazolinyl group,pyrazolinyl group, oxazolinyl group (2-oxazolinyl group, 3-oxazolinylgroup, 4-oxazolinyl group), isoxazolinyl group, thiazolinyl group,isothiazolinyl group, pyranyl group, 2-oxopyranyl group,2-oxo-2,5-dihydrofuranyl group and 1,1-dioxo-1H-isothiazolyl group.Preferable examples include pyrrolyl group, furyl group, thienyl group,imidazolyl group, pyrazolyl group, oxazolyl group, isooxazolyl group,thiazolyl group, isothiazolyl group, pyridyl group,2-oxo-2,5-dihydrofuranyl group and 1,1-dioxo-1H-isothiazolyl group.

As a “heterocyclic group, which is a fused ring”, indolyl group (e.g.,4-indolyl group, 7-indolyl group and the like), isoindolyl group,1,3-dihydro-1,3-dioxoisoindolyl group, benzofuranyl group (e.g.,4-benzofuranyl group, 7-benzofuranyl group and the like), indazolylgroup, isobenzofuranyl group, benzothiophenyl group (e.g.,4-benzothiophenyl group, 7-benzothiophenyl group and the like),benzoxazolyl group (e.g., 4-benzoxazolyl group, 7-benzooxazolyl groupand the like), benzimidazolyl group (e.g., 4-benzimidazolyl group,7-benzimidazolyl group and the like), benzothiazolyl group (e.g.,4-benzothiazolyl group, 7-benzothiazolyl group and the like),indolizinyl group, quinolyl group, isoquinolyl group,1,2-dihydro-2-oxoquinolyl group, quinazolinyl group, quinoxalinyl group,cinnolinyl group, phthalazinyl group, quinolizinyl group, puryl group,pteridinyl group, indolinyl group, isoindolinyl group,5,6,7,8-tetrahydroquinolyl group, 1,2,3,4-tetrahydroquinolyl group,2-oxo-1,2,3,4-tetrahydroquinolyl group, benzo[1,3]dioxolyl group,3,4-methylenedioxypyridyl group, 4,5-ethylenedioxypyrimidinyl group,chromenyl group, chromanyl group, isochromanyl group and the like can bementioned.

It is preferably a fused ring of monocyclic 5- or 6-membered heterocycleand benzene ring. Specific examples thereof include indolyl group,benzofuranyl group, benzothiophenyl group, benzimidazolyl group,benzoxazolyl group, benzothiazolyl group and benzo[1,3]dioxolyl groupand the like.

The “heterocyclic group optionally substituted by 1 to 5 substituentsselected from group A” is a “heterocyclic group” defined above, which isoptionally substituted by 1 to 5, preferably 1 to 3, substituentsselected from “group A” defined above and includes non-substituted“heterocyclic group”.

The “heterocyclic group” is preferably a monocyclic heterocyclecontaining 1 or 2 heteroatoms, or a heterocycle which is a fused ringthereof with a benzene ring.

Specific examples of “heterocyclic group optionally substituted by 1 to5 substituents selected from group A” include pyrrolidinyl group,piperidinyl group, morpholino group, pyrrolyl group, 2-pyrrolyl group,3-pyrrolyl group, 2-furyl group, 3-furyl group, 2-thienyl group,3-thienyl group, 4,5-dichlorothiophen-3-yl group,2-oxo-2,5-dihydrofuran-3-yl group, 1,1-dioxo-1H-isothiazol-5-yl group,4-methylthiazol-5-yl group, imidazolyl group, 2-imidazolyl group,3-imidazolyl group, 4-imidazolyl group, pyrazolyl group, 2-oxazolylgroup, 3-isoxazolyl group, 2-thiazolyl group, 3-isothiazolyl group,3-fluoropyridin-2-yl group, 3-chloropyridin-2-yl group,3-chloro-4-fluoropyridin-2-yl group, 3,5-dichloropyridin-2-yl group,3-pyridyl group, 2-fluoropyridin-3-yl group, 2-chloropyridin-3-yl group,2-chloro-4-fluoropyridin-3-yl group, 2-chloro-5-fluoropyridin-3-ylgroup, 2,5-dichloropyridin-3-yl group, 2-chloro-6-fluoropyridin-3-ylgroup, 2,6-dichloropyridin-3-yl group, 4-pyridyl group,2-fluoropyridin-4-yl group, 2-chloropyridin-4-yl group,2-chloro-3-fluoropyridin-4-yl group, 2,3-difluoropyridin-4-yl group,2,3-dichloropyridin-4-yl group, 2,5-dichloropyridin-4-yl group,2-chloro-6-fluoropyridin-4-yl group, 2,6-dichloropyridin-4-yl group,2-chloro-3,6-difluoropyridin-4-yl group,2-chloro-3,5-difluoropyridin-4-yl group, 2,3,6-trifluoropyridin-4-ylgroup, 2,3,5,6-tetrafluoropyridin-4-yl group, 2-indolyl group, 3-indolylgroup, 4-indolyl group, 7-indolyl group, 2-benzofuranyl group,4-benzofuranyl group, 7-benzofuranyl group, 2-benzothiophenyl group,4-benzothiophenyl group, 7-benzothiophenyl group, 2-benzimidazolylgroup, 4-benzimidazolyl group, 2-benzoxazolyl group, 4-benzoxazolylgroup, 7-benzoxazolyl group, 2-benzothiazolyl group, 4-benzothiazolylgroup, 7-benzothiazolyl group, 2-benzo[1,3]dioxolyl group,4-benzo[1,3]dioxolyl group, 5-benzo[1,3]dioxolyl group and the like.

As ring Cy, 2-pyridyl group and 4-pyridyl group are preferable, as R¹and group B, imidazolyl group, 2-pyridyl group, 2-benzothiophenyl group,morpholino group and 4-methylthiazol-5-yl group are preferable, and asR³² and R³³, pyrrolidinyl group is preferable.

The “C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituentsselected from halogen atom and group B” is a C₁₋₁₀ alkyl groupoptionally substituted by the substituent group selected from-the“halogen atom” defined above and the “group B” defined below, and may bea non-substituted alkyl group. The alkyl moiety is straight chain orbranched chain alkyl group having 1 to 10 carbon atoms. Specificexamples thereof include methyl group, ethyl group, propyl group,isopropyl group, butyl group, isobutyl group, sec-butyl group,tert-butyl group, pentyl group, isopentyl group, 1-methylbutyl group,1-ethylpropyl group, 2-ethylpropyl group, 1,1-dimethylpropyl group,1,2-dimethylpropyl group, tert-pentyl group, hexyl group, isohexylgroup, 1-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutylgroup, 1,3-dimethylbutyl group, 1-ethylbutyl group,1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group,1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group,1-ethyl-1-methylpropyl group, heptyl group, isoheptyl group,1-methylhexyl group, 1,1-dimethylpentyl group, 1,2-dimethylpentyl group,1,3-dimethylpentyl group, 1,4-dimethylpentyl group, 1,1,2-trimethylbutylgroup, 1,1,3-trimethylbutyl group, 1,2,2-trimethylbutyl group,1,2,3-trimethylbutyl group, 1,3,3-trimethylbutyl group, 1-ethylpentylgroup, 1-ethyl-2-methylbutyl group, 1-ethyl-3-methylbutyl group,2-ethyl-1-methylbutyl group, 1-propylbutyl group,1-ethyl-2,2-dimethylpropyl group, 1-isopropyl-2-methylpropyl group,1-isopropyl-1-methylpropyl group, 1,1-diethylpropyl group,1,1,2,2-tetramethylpropyl group, 1-isopropylbutyl group,1-ethyl-1-methylbutyl group, octyl group, nonyl group, decanyl group andthe like, with preference given to straight chain or branched chainalkyl group having 1 to 6 carbon atoms, particularly preferably branchedchain alkyl group having 1 to 6 carbon atoms.

The “group B” is a group consisting of the “C₃₋₁₀ carbon ring groupoptionally substituted by 1 to 5 substituents selected from group A”defined above, the “heterocyclic group optionally substituted by 1 to 5substituents selected from group A” defined above, —OR^(a4), —SR^(a4),—NR^(a4)R^(a5), —CONR^(a4)R^(a5), —SO₂NR^(a4)R^(a5), —COR^(a6),—NR^(a4)COR^(a6), —SO₂R^(a6), —NR^(a4)SO₂R^(a6), —COOR^(a4) and—NR^(a5)COOR^(a6).

As used herein, R^(a4) and R^(a5) are the same or different and each isa hydrogen atom, a “C₁₋₄ alkyl group” defined above, a “C₃₋₁₀ carbonring group optionally substituted by 1 to 5 substituents selected fromgroup A” defined above or a “heterocyclic group optionally substitutedby 1 to 5 substituents selected from group A” defined above, and R^(a6)is a “C₁₋₄ alkyl group” defined above, a “C₃₋₁₀ carbon ring groupoptionally substituted by 1 to 5 substituents selected from group A”defined above or a “heterocyclic group optionally substituted by 1 to 5substituents selected from group A” defined above.

Specific examples of —OR^(a4), —SR^(a4), —NR^(a4)R^(a5),—CONR^(a4)R^(a5), —SO₂NR^(a4)R^(a5), —COR^(a6), —NR^(a4)COR^(a6),—SO₂R^(a6), —NR^(a4)SO₂R^(a6), —COOR^(a4) and —NR^(a5)COOR^(a6) includesubstituents recited in the definitions of “—OR^(a1)”, “—SR^(a1)”,“—NR^(a1)R^(a2)”, “—CONR^(a1)R^(a2)”, “—SO₂NR^(a1)R^(a2)”, “—COR^(a3)”,“—NR^(a1)COR^(a3)”, “—SO₂R^(a3)”, “—NR^(a1)SO₂R^(a3)”, “—COOR^(a1)” and“—NR^(a2)COOR^(a3)” for “group A”, respectively, and the like.

Specific examples of “C-₁₀ alkyl group optionally substituted by 1 to 3substituents selected: from halogen atom and group B” include methylgroup, ethyl group, propyl group, isopropyl group, butyl group, isobutylgroup, sec-butyl group, tert-butyl group, pentyl group, isopentyl group,1-methylbutyl group, 1-ethylpropyl group, 2-ethylpropyl group,1,1-dimethylpropyl group, 1,2-dimethylpropyl group, tert-pentyl group,hexyl group, isohexyl group, 1-methylpentyl group, 1,1-dimethylbutylgroup, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 1-ethylbutylgroup, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group,1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group,1-ethyl-1-methylpropyl group, heptyl group, isoheptyl group,1-methylhexyl group, 1,1-dimethylpentyl group, 1,2-dimethylpentyl group,1,3-dimethylpentyl group, 1,4-dimethylpentyl group, 1,1,2-trimethylbutylgroup, 1,1,3-trimethylbutyl group, 1,2,2-trimethylbutyl group,1,2,3-trimethylbutyl group, 1,3,3-trimethylbutyl group, 1-ethylpentylgroup, 1-ethyl-2-methylbutyl group, 1-ethyl-3-methylbutyl group,2-ethyl-1-methylbutyl group, 1-propylbutyl group,1-ethyl-2,2-dimethylpropyl group, 1-isopropyl-2-methylpropyl group,1-isopropyl-1-methylpropyl group, 1,1-diethylpropyl group,1,1,2,2-tetramethylpropyl group, 1-isopropylbutyl group,1-ethyl-1-methylbutyl group, fluoromethyl group, trifluoromethyl group,chloroethyl group, 2-fluoroethyl group, 2-chloroethyl group,3-fluoropropyl group, 2-chloropropyl group, 2,2,2-trifluoroethyl group,2-hydroxyethyl group, 2-hydroxypropyl group, 2-hydroxy-1-methylethylgroup, 2-hydroxy-1,1-dimethylethyl group, 1-(hydroxymethyl)propyl group,3-hydroxypropyl group, 2-hydroxybutyl group, 4-hydroxybutyl group,2-hydroxypentyl group, 5-hydroxypentyl group, 2,3-dihydroxypropyl group,2,3-dihydroxybutyl group, 2-hydroxy-1-(hydroxymethyl)ethyl group,2-hydroxy-2-methylpropyl group, 1-(hydroxymethyl)butyl group,1-(hydroxymethyl)-2-methylpropyl group,1-(hydroxymethyl)-2,2-dimethylpropyl group,1-(hydroxymethyl)-2-methylbutyl group, 2-hydroxy-1-phenylethyl group,2-hydroxy-2-phenylethyl group, 1-(hydroxymethyl)-2-phenylethyl group,3-methyl-1-(hydroxymethyl)butyl group, 2-ethyl-1-(hydroxymethyl)butylgroup, 3-hydroxy-1-methylpropyl group, 1,1-dimethyl-3-hydroxypropylgroup, 1,2-dimethyl-3-hydroxypropyl group, 1-isopropyl-3-hydroxypropylgroup, 2,2-dimethyl-1-(2-hydroxyethyl)propyl group,1-ethyl-3-hydroxypropyl group, 2-hydroxy-1-isopropylpropyl group,1-ethyl-1-(hydroxymethyl)propyl group, 1,1-dimethyl-2-hydroxypropylgroup, 1,2-dimethyl-2-hydroxypropyl group, 1-ethyl-2-hydroxypropylgroup, 4-hydroxy-1-methylbutyl group,2-ethyl-1-(hydroxymethyl)-2-methylbutyl group,3,3-dimethyl-1-(hydroxymethyl)butyl group, 1-(hydroxymethyl)pentylgroup, 4-methyl-1-(hydroxymethyl)pentyl group, methoxymethyl group,2-methoxyethyl group, methylsulfanylmethyl group,2-(methylsulfanyl)ethyl group, 2-aminoethyl group,2-(dimethylamino)ethyl group, carboxymethyl group, 2-carboxyethyl group,2-carboxypropyl group, 3-carboxypropyl group, carbamoylmethyl group,2-carbamoylethyl group, methylaminocarbonylmethyl group,dimethylaminocarbonylmethyl group, 2-(phenylaminocarbonyl)ethyl group,2-oxopropyl group, methylsulfonylmethyl group, 2-(methylsulfonyl)ethylgroup, sulfamoylmethyl group, methylaminosulfonylmethyl group,dimethylaminosulfonylmethyl group, tert-butylaminosulfonylmethyl group,2-(acetylamino)ethyl group, 2-(methylsulfonylamino)ethyl group,2-(ethoxycarbonylamino)ethyl group, benzyl group, phenethyl group,3-phenylpropyl group, 4-phenylbutyl group, 2-biphenylmethyl group,3,4-dichlorobenzyl group, 2-hydroxy-2-phenylethyl group,cyclopentylmethyl group, cyclohexylmethyl group, 2-cyclohexylethylgroup, 1-cyclohexyl-2-hydroxyethyl group,1-cyclohexylmethyl-2-hydroxyethyl group, phenylaminocarbonylmethylgroup, 2-pyridin-2-ylethyl group, 2-imidazol-1-ylethyl group,2-benzothiophen-2-ylethyl group, 2-morpholinoethyl group,2-(4-methylthiazolin-5-yl)ethyl group, 1-carboxyethyl group,1-carbamoylethyl group, 1-carboxy-2-methylpropyl group,1-carbamoyl-2-methylpropyl group, 2-hydroxy-1-(hydroxymethyl)propylgroup, 1-(hydroxymethyl)-2-mercaptoethyl group,1-(hydroxymethyl)-3-(methylsulfanyl)propyl group,2-carboxy-1-(hydroxymethyl)ethyl group,2-carbamoyl-1-(hydroxymethyl)ethyl group,2-(indol-3-yl)-1-(hydroxymethyl)ethyl group,2-(imidazol-4-yl)-1-(hydroxymethyl)ethyl group,2-(4-hydroxyphenyl)-1-(hydroxymethyl)ethyl group,3-carbamoyl-1-(hydroxymethyl)propyl group,5-amino-1-(hydroxymethyl)pentyl group and the like.

R¹ is preferably methyl group, ethyl group, propyl group, isopropylgroup, butyl group, isobutyl group, tert-butyl group, 2-fluoroethylgroup, 2,2,2-trifluoroethyl group, 2-hydroxyethyl group, 2-hydroxypropylgroup, 3-hydroxypropyl group, 4-hydroxybutyl group, 5-hydroxypentylgroup, 2,3-dihydroxypropyl group, 2-hydroxy-1-methylethyl group,2-hydroxy-1,1-dimethylethyl group, 2-hydroxy-1-(hydroxymethyl)ethylgroup, 1-(hydroxymethyl)propyl group, 2-hydroxy-2-methylpropyl group,1-(hydroxymethyl)butyl group, 1-(hydroxymethyl)-2-methylpropyl group,1-(hydroxymethyl)-2,2-dimethylpropyl group,1-(hydroxymethyl)-2-methylbutyl group, 1-(hydroxymethyl)-3-methylbutylgroup, 2-hydroxy-1-phenylethyl group, 2-hydroxy-2-phenylethyl group,1-(hydroxymethyl)-2-phenylethyl group, 2-methoxyethyl group,methylsulfanylmethyl group, 2-(methylsulfanyl)ethyl group, 2-aminoethylgroup, 2-(dimethylamino)ethyl group, carboxymethyl group, 2-carboxyethylgroup, 3-carboxypropyl group, carbamoylmethyl group, 2-carbamoylethylgroup, methylaminocarbonylmethyl group, dimethylaminocarbonylmethylgroup, 2-(phenylaminocarbonyl)ethyl group, 2-oxopropyl group,methylsulfonylmethyl group, 2-(methylsulfonyl)ethyl group,sulfamoylmethyl group, methylaminosulfonylmethyl group,dimethylaminosulfonylmethyl group, tert-butylaminosulfonylmethyl group,2-(acetylamino)ethyl group, 2-(methylsulfonylamino)ethyl group,2-(ethoxycarbonylamino)ethyl group, benzyl group, phenethyl group,3-phenylpropyl group, 4-phenylbutyl group, 2-biphenylmethyl group,3,4-dichlorobenzyl group, cyclopentylmethyl group, cyclohexylmethylgroup, 1-cyclohexyl-2-hydroxyethyl group,1-cyclohexylmethyl-2-hydroxyethyl group, 2-pyridin-2-ylethyl group,2-imidazol-1-ylethyl group, 2-morpholinoethyl group,2-(4-methylthiazolin-5-yl)ethyl group or benzothiophen-2-ylmethyl group,particularly preferably alkyl group branched at the 1-position and/oralkyl group substituted by hydroxy group. Specific examples thereofinclude 2-hydroxy-1-methylethyl group, 1-(hydroxymethyl)-2-methylpropylgroup, 1-(hydroxymethyl)-2,2-dimethylpropyl group,1-(hydroxymethyl)-2-methylbutyl group, 2-hydroxy-1-(hydroxymethyl)ethylgroup and 2-phenyl-1-(hydroxymethyl)ethyl group. When these particularlypreferable substituents are in optically active forms, S form is morepreferable.

R³² and R³³ are preferably methyl group, ethyl group and trifluoromethylgroup, and R^(a7) and R^(a8) are preferably methyl group, ethyl group,propyl group, isopropyl group, 2-hydroxyethyl group, 3-hydroxypropylgroup and cyclohexylmethyl group, more preferably methyl group, ethylgroup and isopropyl group, and particularly preferably methyl group.

The ring Cy in the formula [I] is preferably a “C₃₋₁₀ carbon ring groupoptionally substituted by 1 to 5 substituents selected from group A”defined above, more preferably

wherein R⁴, R⁵, R⁶ and m are as defined above. A more preferableembodiment here is the same as the 4-oxoquinoline compound representedby the formula [II], wherein m is preferably 0 or 1, more preferably 0.

The group A for ring Cy is preferably cyano group, phenyl group, nitrogroup, “halogen atom” defined above, “C₁₋₄ alkyl group” defined above,“halo C₁₋₄ alkyl group” defined above, “halo C₁₋₄ alkyloxy group”defined above, “—OR^(a1)” defined above, “—SR^(a1)” defined above,“—NR^(a1)R^(a2)” defined above, “—CONR^(a1)R^(a2)” defined above,“—SO₂NR^(a1)R^(a2)” defined above, “—NR^(a1)COR^(a3)” defined above,“—SO₂R^(a3)” defined above or “—NR^(a1)SO₂R^(a3)” defined above, morepreferably cyano group, phenyl group, nitro group, “halogen atom”, “C₁₋₄alkyl group”, “halo C₁₋₄ alkyl group”, “halo C₁₋₄ alkyloxy group”,“—OR^(a1)”, “—SR^(a1)”, “—NR^(a1)R^(a2)”, “—SO₂R^(a3)”,“—SO₂NR^(a1)R^(a2)” or “—NR^(a1)COR^(a3)”, and particularly preferably“halogen atom” defined above.

The ring Cy is more preferably

wherein R^(6′), R^(6″) and R^(6′″) are substituents selected fromhydrogen atom and “group A” defined above, and R⁴ and R⁵ are as definedabove.

R⁴ is preferably phenyl group, “halogen atom” defined above, “C₁₋₄ alkylgroup” defined above, “halo C₁₋₄ alkyloxy group” defined above,“—OR^(a1)” defined above, “—NR^(a1)R^(a2)” defined above,“—SO₂NR^(a1)R^(a2)” defined above, “—NR^(a1)COR^(a3)” defined above,“—SO₂R^(a3)” defined above, “—COOR^(a1)” defined above or“—NR^(a1)SO₂R^(a3)” defined above,

more preferably “halogen atom”, “C₁₋₄ alkyl group”, “halo C₁₋₄ alkyloxygroup”, “—OR^(a1)” or “—NR^(a1)R^(a2)”, and particularly preferably“halogen atom” defined above,

R⁵ is preferably hydrogen atom, cyano group, nitro group, “halogen atom”defined above, “C₁₋₄ alkyl group” defined above, “halo C₁₋₄ alkyl group”defined above, “—OR^(a1)”, defined above, “—SR^(a1)” defined above,“—NR^(a1)R^(a2)” defined above, “CONR^(a1)R^(a2)” defined above,“—SO₂NR^(a1)R^(a2)” defined above or “—NR^(a1)COR^(a3)” defined above,

more preferably hydrogen atom, “halogen atom” or “C₁₋₄ alkyl group”, andparticularly preferably “halogen atom”.

R⁶ is preferably “halogen atom”, “C₁₋₄ alkyl group” defined above,“—SO₂R^(a3)” defined above, “—OR^(a1)” defined above or “—SR^(a1)”defined above, more preferably “halogen atom”.

R^(6′) and R^(6′″) are preferably the same or different and each ishydrogen atom or “halogen atom” defined above, R^(6″) is preferablyhydrogen atom, “halogen atom” defined above, “C₁₋₄ alkyl group” definedabove, “—SO₂R^(a3)” defined above, “—OR^(a1)” defined above or“—SR^(a1)” defined above, more preferably, hydrogen atom, “halogenatom”, “C₁₋₄ alkyl group” defined above or “—SR^(a1)” defined above, andmore preferably hydrogen atom.

R¹ is preferably “C₃₋₁₀ carbon ring group optionally substituted by 1 to5 substituents selected from group A” defined above, “heterocyclic groupoptionally substituted by 1 to 5 substituents selected from group A”defined above, “—OR^(a4)” defined above (here, it is concretelypreferably methoxy group), “—NR^(a4)R^(a5)” defined above (here, it isconcretely preferably amino group, methylamino group, ethylamino groupor dimethylamino group), “—NR^(a4)COR^(a6)” defined above (here, it isconcretely preferably acetylamino group), “—NR^(a4)SO₂R^(a6)” definedabove (here, it is concretely preferably, methylsulfonylamino group orN-methyl-N-(methylsulfonyl)amino group), “—NR^(a5)COOR^(a6)” definedabove (here, it is concretely preferably methoxycarbonylamino group) or“C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituentsselected from halogen atom and group B” defined above, more preferably,“C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituentsselected from group A” defined above or “C₁₋₁₀ alkyl group optionallysubstituted by 1 to 3 substituents selected from halogen atom and groupB”, more preferably “C₁₋₁₀ alkyl group optionally substituted by 1 to 3substituents selected from halogen atom and group B” defined above.

R² is preferably hydrogen atom.

R³¹ is preferably hydrogen atom, cyano group, “halogen atom” definedabove, hydroxy group or “C₁₋₄ alkoxy group” defined above, morepreferably hydrogen atom, cyano group, “halogen atom” defined above or“C₁₋₄ alkoxy group” defined above, more preferably hydrogen atom, cyanogroup or “C₁₋₄ alkoxy group” defined above, particularly preferablyhydrogen atom.

R³² is preferably hydrogen atom, cyano group, “halogen atom” definedabove, “heterocyclic group optionally substituted by 1 to 5 substituentsselected from group A” defined above, “C₁₋₁₀ alkyl group optionallysubstituted by 1 to 3 substituents selected from halogen atom and groupB” defined above, “—OR^(a7)” defined above, “—SR^(a7)” defined above,“—NR^(a7)R^(a8)” defined above, “—COOR^(a10)” defined above or“—N═CH—NR^(a10)R^(a11)” defined above, more preferably hydrogen atom,“—OR^(a7)” defined above, “—SR^(a7)” defined above or “—NR^(a7)R^(a8)”defined above, more preferably hydrogen atom or “—OR^(a7)” definedabove, particularly preferably “—OR^(a7)”.

R³³ is preferably hydrogen atom, “C₁₋₁₀ alkyl group optionallysubstituted by 1 to 3 substituents selected from halogen atom and groupB” defined above, “—OR^(a7)” defined above or “—NR^(a7)R^(a8)” definedabove, more preferably hydrogen atom, “—OR^(a7)” defined above or“—NR^(a7)R^(a8)” defined above, more preferably hydrogen atom or“—OR^(a7)” defined above, particularly preferably hydrogen atom.

It is preferable that one of R³² and R³³ be hydrogen atom, and the otherbe “—OR^(a7)” defined above.

It is preferable that R³¹ be hydrogen atom and R³² or R³³ be other thanhydrogen atom.

The “pharmaceutically acceptable salt thereof” may be any as long as itforms a non-toxic salt with a compound of the above-mentioned formula[I] or [II]. For example, it can be obtained by reaction with aninorganic acid such as hydrochloric acid, sulfuric acid, phosphoricacid, hydrobromic acid and the like; an organic acid such as oxalicacid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid,succinic acid, tartaric acid, acetic acid, trifluoroacetic acid,gluconic acid, ascorbic acid, methylsulfonic acid, benzylsulfonic acidand the like; an inorganic base such as sodium hydroxide, potassiumhydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxideand the like; an organic base such as methylamine, diethylamine,triethylamine, triethanolamine, ethylenediamine,tris(hydroxymethyl)methylamine, guanidine, choline, cinchonine and thelike; or an amino acid such as lysin, arginine, alanine and the like.The present invention encompasses water-containing products, hydratesand solvates of each compound.

In addition, the compounds represented by the above-mentioned formulas[I] and [II] have various isomers. For example, E form and Z form arepresent as geometric isomers, and when an asymmetric carbon atom exists,enantiomer and diastereomer are present as stereoisomers based thereon,and tautomer can be present. Accordingly, the present inventionencompasses all these isomers and mixtures thereof. The compound of thepresent invention is preferably isolated and purified from variousisomers, byproducts, metabolites or prodrugs, where one having a purityof 90% or above is preferable and one having a purity of 95% or above ismore preferable.

The present invention also encompasses prodrugs and metabolites of eachcompound.

By the “prodrug” is meant a derivative of the compound of the presentinvention, which has a chemically or metabolically decomposable groupand which, after administration to a body, restores to the originalcompound to show its inherent efficacy, including a complex and a saltfree of covalent bond.

The prodrug is utilized for, for example, improving absorption by oraladministration or targeting of a target site.

As the site to be modified, highly reactive functional groups in thecompound of the present invention, such as hydroxyl group, carboxylgroup, amino group, thiol group and the like, are mentioned.

Examples of the hydroxyl-modifying group include acetyl group, propionylgroup, isobutyryl group, pivaloyl group, benzoyl group, 4-methylbenzoylgroup, dimethylcarbamoyl group, sulfo group and the like. Examples ofthe carboxyl-modifying group include ethyl group, pivaloyloxymethylgroup, 1-(acetyloxy)ethyl group, 1-(ethoxycarbonyloxy)ethyl group,1-(cyclohexyloxycarbonyloxy)ethyl group, carboxylmethyl group,(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, phenyl group, o-tolylgroup and the like. Examples of the amino-modifying group includehexylcarbamoyl group, 3-methylthio-1-(acetylamino)propylcarbonyl group,1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl group,(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group and the like.

The compound of the present invention can be administered to a mammal(human, mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, swine andthe like) as an anti-HIV agent, an integrase inhibitor, an antiviralagent and the like.

When the compound of the present invention is used as a pharmaceuticalpreparation, it is admixed with pharmaceutically acceptable carriers,excipients, diluents, extending agents, disintegrants, stabilizers,preservatives, buffers, emulsifiers, flavoring agents, coloring agents,sweetening agents, thickeners, correctives, dissolution aids, and otheradditives, that are generally known per se, such as water, vegetableoil, alcohol (e.g., ethanol or benzyl alcohol etc.), polyethyleneglycol, glycerol triacetate, gelatin, carbohydrate (e.g., lactose,starch etc.), magnesium stearate, talc, lanolin, petrolatum and thelike, formed into tablet, pill, powder, granule, suppository, injection,eye drop, liquid, capsule, troche, aerosol, elixir, suspension,emulsion, syrup and the like by a conventional method, and administeredsystemically or topically, and orally or parenterally.

While the dose varies depending on age, body weight, symptom, treatmenteffect, administration method and the like, it is generally 0.01 mg to 1g per administration for an adult, which is given once to several timesa day orally or in a dosage form of an injection such as intravenousinjection and the like.

An anti-HIV agent is generally required to sustain its effect for a longtime, so that can be effective not only for temporal suppression ofviral growth but also for prohibition of viral re-growth. This meansthat a long term administration is necessary and that a high single dosemay be frequently inevitable to sustain effect for a longer periodthrough the night. Such long term and high dose administration increasesthe risk of causing side effects.

In view of this, one of the preferable modes of the 4-oxoquinolinecompound of the present invention is such compound permitting highabsorption by oral administration, and such compound capable ofmaintaining blood concentration of the administered compound for anextended period of time.

By the “prophylaxis of AIDS” is meant, for example, administration of apharmaceutical agent to an individual who tested HIV positive but hasnot yet developed the disease state of AIDS, administration of apharmaceutical agent to an individual who shows an improved diseasestate of AIDS after treatment but who carries HIV still to be eradicatedand whose relapse of AIDS is worried, and administration of apharmaceutical agent before the infection of HIV out of a fear ofpossible infection.

Examples of the “other anti-HIV agents” and “other anti-HIV activesubstance” to be used for a multiple drug combination therapy include ananti-HIV antibody, an HIV vaccine, immunostimulants such as interferonand the like, an HIV ribozyme, an HIV antisense drug, a reversetranscriptase inhibitor, a protease inhibitor, an inhibitor of bondbetween a bond receptor (CD4, CXCR4, CCR5 and the like) of a host cellrecognized by virus and the virus, and the like.

Specific examples of the HIV reverse transcriptase inhibitor includeRetrovir(R) (zidovudine), Epivir(R) (lamivudine), Zerit(R)(sanilvudine), Videx(R) (didanosine), Hivid(R) (zalcitabine), Ziagen(R)(abacavir sulfate), Viramune(R) (nevirapine), Stocrin(R) (efavirenz),Rescriptor(R) (delavirdine mesylate), Combivir(R)(zidovudine+lamivudine), Trizivir(R) (abacavirsulfate+lamivudine+zidovudine), Coactinon(R) (emivirine),Phosphonovir(R), Coviracil(R), alovudine (3′-fluoro-3′-deoxythymidine),Thiovir (thiophosphonoformic acid), Capravirin(5-[(3,5-dichlorophenyl)thio]-4-isopropyl-1-(4-pyridylmethyl)imidazole-2-methanolcarbamic acid), Tenofovir disoproxil fumarate((R)-[[2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acidbis(isopropoxycarbonyloxymethyl)ester fumarate), DPC-083((4S)-6-chloro-4-[(1E)-cyclopropylethenyl]-3,4-dihydro-4-trifluoromethyl-2(1H)-quinazolinone),DPC-961((4S)-6-chloro-4-(cyclopropylethynyl)-3,4-dihydro-4-(trifluoromethyl)-2(1H)-quinazolinone),DAPD ((−)-β-D-2,6-diaminopurine dioxolane), Immunocal, MSK-055, MSA-254,MSH-143, NV-01, TMC-120, DPC-817, GS-7340, TMC-125, SPD-754, D-A4FC,capravirine, UC-781, emtricitabine, alovudine, Phosphazid, UC-781,BCH-10618, DPC-083, Etravirine, BCH-13520, MIV-210, Abacavirsulfate/lamivudine, GS-7340, GW-5634, GW-695634 and the like, wherein(R) means a registered trademark (hereinafter the same) and the names ofother pharmaceutical agents are general names.

Specific examples of the HIV protease inhibitor include Crixivan(R)(indinavir sulfate ethanolate), saquinavir, Invirase(R) (saquinavirmesylate), Norvir(R) (ritonavir), Viracept(R) (nelfinavir mesylate),lopinavir, Prozei(R) (amprenavir), Kaletra(R) (ritonavir+lopinavir),mozenavir dimesylate([4R-(4α,5α,6β)]-1-3-bis[(3-aminophenyl)methyl]-hexahydro-5,6-dihydroxy-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-onedimethanesulfonate), tipranavir(3′-[(1R)-1-[(6R)-5,6-dihydro-4-hydroxy-2-oxo-6-phenylethyl-6-propyl-2H-pyran-3-yl)propyl]-5-(trifluoromethyl)-2-pyridinesulfonamide),lasinavir(N-[5(S)-(tert-butoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxybenzyl)hexanoyl]-L-valine2-methoxyethylenamide), KNI-272((R)-N-tert-butyl-3-[(2S,3S)-2-hydroxy-3-N-[(R)-2-N-(isoquinolin-5-yloxyacetyl)amino-3-methylthiopropanoyl]amino-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide),GW-433908, TMC-126, DPC-681, buckminsterfullerene, MK-944A (MK944(N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-[4-(2-benzo[b]furanylmethyl)-2(S)-(tert-butylcarbamoyl)piperazin-1-yl]pentanamide)+indinavirsulfate), JE-2147([2(S)-oxo-4-phenylmethyl-3(S)-[(2-methyl-3-oxy)phenylcarbonylamino]-1-oxabutyl]-4-[(2-methylphenyl)methylamino)carbonyl-4(R)-5,5-dimethyl-1,3-thiazole),BMS-232632((3S,8S,9S,12S)-3,12-bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedicarboxylicacid dimethyl ester), DMP-850((4R,5S,6S,7R)-1-(3-amino-1H-indazol-5-ylmethyl)-4,7-dibenzyl-3-butyl-5,6-dihydroxyperhydro-1,3-diazepin-2-one),DMP-851, RO-0334649, Nar-DG-35, R-944, VX-385, TMC-114, Tipranavir,Fosamprenavir sodium, Fosamprenavir-calcium, Darunavir, GW-0385, R-944,RO-033-4649, AG-1859 and the like.

The HIV integrase inhibitor is exemplified by S-1360, L-870810 and thelike, the DNA polymerase inhibitor or DNA synthesis inhibitor isexemplified by Foscavir(R), ACH-126443(L-2′,3′-didehydro-dideoxy-5-fluorocytidine), entecavir((1S,3S,4S)-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]guanine),calanolide A([10R-(10α,11β,12α)]-11,12-dihydro-12-hydroxy-6,6,10,11-tetramethyl-4-propyl-2H,6H,10H-benzo[1,2-b:3,4-b′:5,6-b″]tripyran-2-one),calanolide B, NSC-674447 (1,1′-azobisformamide), Iscador (viscum alubmextract), Rubutecan and the like, the HIV antisense drug is exemplifiedby HGTV-43, GEM-92 and the like, the anti-HIV antibody or other antibodyis exemplified by NM-01, PRO-367, KD-247, Cytolin(R), TNX-355 (CD4antibody), AGT-1, PRO-140 (CCR⁵ antibody), Anti-CTLA-4 MAb and the like,the HIV vaccine or other vaccine is exemplified by ALVAC(R), AIDSVAX(R),Remune(R), HIV gp41 vaccine, HIV gp120 vaccine, HIV gp140 vaccine, HIVgp160 vaccine, HIV p17 vaccine, HIV p24 vaccine, HIV p55 vaccine,AlphaVax Vector System, canarypox gp160 vaccine, AntiTat, MVA-F6 Nefvaccine, HIV rev vaccine, C4-V3 peptide, p2249f, VIR-201, HGP-30W,TBC-3B, PARTICLE-3B and the like, Antiferon (interferon-α vaccine) andthe like, the interferon or interferon agonist is exemplified bySumiferon(R), MultiFeron(R), interferon-τ, Reticulose, Human leukocyteinterferon alpha and the like, the CCR⁵ antagonist is exemplified bySCH-351125 and the like, the pharmaceutical agent acting on HIV p24 isexemplified by GPG-NH2 (glycyl-prolyl-glycinamide) and the like, the HIVfusion inhibitor is exemplified by FP-21399(1,4-bis[3-[(2,4-dichlorophenyl)carbonylamino]-2-oxo-5,8-disodiumsulfonyl]naphthyl-2,5-dimethoxyphenyl-1,4-dihydrazone), T-1249,Synthetic Polymeric Construction No 3, pentafuside, FP-21399, PRO-542,Enfuvirtide and the like, the IL-2 agonist or antagonist is exemplifiedby interleukin-2, Imunace(R), Proleukin(R), Multikine(R), Ontak(R) andthe like, the TNF-α antagonist is exemplified by Thalomid(R)(thalidomide), Remicade(R) (infliximab), curdlan sulfate and thelike,the α-glucosidase inhibitor is exemplified by Bucast(R) and thelike, the purine nucleoside phosphorylase inhibitor is exemplified bypeldesine(2-amino-4-oxo-3H,5H-7-[(3-pyridyl)methyl]pyrrolo[3,2-d]pyrimidine) andthe like, the apoptosis agonist or inhibitor is exemplified by ArkinZ(R), Panavir(R), Coenzyme Q10(2-deca(3-methyl-2-butenylene)-5,6-dimethoxy-3-methyl-p-benzoquinone)and the like, the cholinesterase inhibitor is exemplified by Cognex(R)and the like, and the immunomodulator is exemplified by Imunox(R),Prokine(R), Met-enkephalin(6-de-L-arginine-7-de-L-arginine-8-de-L-valinamide-adrenorphin), WF-10(10-fold dilute tetrachlorodecaoxide solution), Perthon, PRO-542, SCH-D,UK-427857, AMD-070, AK-602 and the like.

In addition, Neurotropin(R), Lidakol(R), Ancer 20(R), Ampligen(R),Anticort(R), Inactivin(R) and the like, PRO-2000, Rev M10 gene, HIVspecific cytotoxic T cell (CTL immunotherapy, ACTG protocol 080 therapy,CD4-ζ gene therapy), SCA binding protein, RBC-CD4 complex, Motexafingadolinium, GEM-92, CNI-1493, (±)-FTC, Ushercell, D2S, BufferGel(R),VivaGel(R), Glyminox vaginal gel, sodium lauryl sulfate, 2F5, 2F5/2G12,VRX-496, Ad5gag2, BG-777, IGIV-C, BILR-255 and the like are exemplified.

As the “other anti-HIV agents” and “other anti-HIV active substance” tobe used for a multiple drug combination therapy with the compound of thepresent invention, preferred are a reverse transcriptase inhibitor and aprotease inhibitor. Two or three, or even a greater number ofpharmaceutical agents can be used in combination, wherein a combinationof pharmaceutical agents having different action mechanisms is one ofthe preferable embodiments. In addition, selection of pharmaceuticalagents free of side effect duplication is preferable.

Specific combination of pharmaceutical agents include a combination of agroup consisting of Efavirenz, Tenofovir, Emtricitabine, Indinavir,Nelfinavir, Atanazavir, Ritonavir+Indinavir, Ritonavir+Lopinavir,Ritonavir+Saquinavir, Didanosine+Lamivudine, Zidovudine+Didanosine,Stavudine+Didanosine, Zidovudine+Lamivudine, Stavudine+Lamivudine, andEmtriva and the 4-oxoquinoline compound [I] of the present invention(Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adultsand Adolescents. Aug. 13, 2001). Particularly preferably, two drugtherapy by the combination with Efavirenz, Indinavir, Nelfinavir,Tenofovir, Emtricitabine, Zidovudine and Lamivudine, and three drugtherapy by the combination with Zidovudine+Lamivudine,Tenofovir+Lamivudine, Tenofovir+Zidovudine, Tenofovir+Efavirenz,Tenofovir+Nelfinavir, Tenofovir+Indinavir, Tenofovir+Emtricitabine,Emtricitabine+Lamivudine, Emtricitabine+Zidovudine,Emtricitabine+Efavirenz, Emtricitabine+Nelfinavir,Emtricitabine+Indinavir, Nelfinavir+Lamivudine, Nelfinavir+Zidovudine,Nelfinavir+Efavirenz, Nelfinavir+Indinavir, Efavirenz+Lamivudine,Efavirenz+Zidovudine, and Efavirenz+Indinavir can be mentioned.

Some examples of the production methods of the compounds used forembodiment of the present invention are shown in the following. However,the production method of the compounds of the present invention is notlimited to these examples.

Even in the absence of description in the production method, efficientproduction can be afforded, where necessary, by introducing a protectinggroup into a functional group followed by deprotection in a subsequentstep, by using a compound with a functional group as a precursor in eachstep and converting the group to a desired functional group in asuitable step, by exchanging the order of respective production methodsand steps, or by other method.

The workup in each step can be applied by a typical method, whereinisolation and purification is performed by selecting or combiningconventional methods as necessary, such as crystallization,recrystallization, distillation, partitioning, silica gelchromatography, preparative HPLC and the like.

wherein Hal is a halogen atom such as chlorine atom, bromine atom andthe like; Hal¹ is a halogen atom such as bromine atom, iodine atom andthe like; R^(1A) is “C₁₋₁₀ alkyl group optionally substituted by 1 to 3substituents selected from halogen atom and group B” defined above;R^(2A) is “C₁₋₄ alkyl group” defined above, which is preferably methylgroup or ethyl group; in compound [6], each R^(2A) may be different butpreferably the same; (R³)_(n) is a substituent of any of R³¹, R³² andR³³, which may be the same or different; n is an integer of 1 to 3;where the substituent R³ does not simultaneously substitute at both ofthe * positions, and other symbols are as defined above.Step 1

Under an argon or nitrogen stream, zinc powder and 1,2-dibromoethane arereacted in a solvent with heating, and trimethylsilyl chloride is addedto allow reaction. Then, to the reaction solution is added a solution ofcompound [1] to allow reaction to give compound [2].

As preferable solvents, ether solvents such as 1,4-dioxane, diethylether, 1,2-dimethoxyethane, tetrahydrofuran (THF) and the like;hydrocarbon solvents such as benzene, toluene, hexane, xylene and thelike; and the like can be mentioned.

Step 2

The compound [2] is reacted with compound [3] in a solvent in thepresence of a catalyst and, where necessary, a ligand such astriphenylphosphine, tri(2-furyl)phosphine and the like, and under anargon or nitrogen stream with cooling or with heating to give compound[4].

As the catalyst, palladium catalysts such asbis(dibenzylideneacetone)palladium,tris(dibenzylideneacetone)dipalladium,dichlorobis(triphenylphosphine)palladium,dichlorobis(benzonitrile)palladium, dichloroethylenediamine palladium,palladium acetate, tetrakis(triphenylphosphine)palladium and the like,nickel catalyst and the like can be mentioned.

As preferable solvents, ether solvents such as 1,4-dioxane, diethylether, 1,2-dimethoxyethane, tetrahydrofuran (THF) and the like;hydrocarbon solvents such as benzene, toluene, hexane, xylene and thelike and the like can be mentioned.

Step 3

The compound [4] is reduced by a conventional method such as reductionwith zinc or iron under neutral or alkaline conditions; iron and acid;tin or tin(II) chloride and conc. hydrochloric acid; alkali sulfide;alkaline hydrosulfite and the like, catalytic reduction under a hydrogenatmosphere, and the like to give compound [5].

For example, to compound [4] are added acetic acid and zinc powder withcooling, and the mixture is reacted at room temperature to give compound[5]. Alternatively, palladium-carbon is added to a solution of compound[4] in a mixed solvent of THF and methanol and the mixture is reactedunder a hydrogen atmosphere at room temperature to give compound [5].

Step 4

The compound [5] is reacted with compound [6] in a solvent with heating.

As preferable solvents, alcohol solvents such as methanol, ethanol,n-propanol, isopropanol and the like; hydrocarbon, solvents such asbenzene, toluene, hexane, xylene and the like; halogenated solvents suchas dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and the like and a mixed solventsthereof can be mentioned.

Then, after removal of the solvent, the residue is reacted in a solventsuch as diphenyl ether or a mixture of diphenyl ether and diphenyl, suchas Dowtherm A (trademark, Fluka) and the like, with heating to givecompound [7].

Step 5

The compound [7] is reacted with compound [8] in a solvent in thepresence of a base to give compound [I-1].

As the base, potassium carbonate, sodium carbonate, lithium hydride,sodium hydride, potassium hydride and the like can be mentioned, withpreference given to potassium carbonate.

As the solvents, hydrocarbon solvents such as benzene, toluene, hexane,xylene and the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and the like; polar solvents suchas dimethylformamide, dimethyl sulfoxide, acetonitrile and the like anda mixed solvent thereof can be mentioned.

Step 6

The compound [I-1] is subjected to hydrolysis in a solvent at roomtemperature or with heating under basic conditions with sodiumhydroxide, potassium hydroxide, lithium hydroxide and the like, or underacidic conditions with hydrochloric acid, sulfuric acid and the like togive compound [I-2].

As the solvents, alcohol solvents such as methanol, ethanol, n-propanol,isopropanol and the like; hydrocarbon solvents such as benzene, toluene,hexane, xylene and the like; halogenated solvents such asdichloromethane, carbon tetrachloride, 1,2-dichloroethane and the like;ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane,tetrahydrofuran and the like; polar solvents such as dimethylformamide,dimethyl sulfoxide, acetonitrile and the like; water and a mixed solventthereof can be mentioned.

By a reaction in the same manner as in Production Method 1-1 usingcompound [20] represented by

instead of compound [3], compound [I] can be obtained. Production Method1-2 Example of production method using compound [9] in which ahydroxyl-protecting group has been introduced

wherein r is an integer of 1 to 6, R^(P1) is a hydroxyl-protectinggroup, and other symbols are as defined above.Step 1

The compound [7] obtained in the same manner as in Production Method 1-1and compound [9] are reacted in the same manner as in Production Method1-1, Step 5 to give compound [10].

Step 2

The compound [10] is deprotected by a conventional method to givecompound [I-3].

As the hydroxyl-protecting group, acetyl group, methyloxycarbonyl group,methoxymethyl group, methoxyethoxymethyl group, trimethylsilyl group,tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group and thelike can be mentioned.

For example, when R^(P1) is acetyl group or methyloxycarbonyl group, areaction with heating in the presence of a base such as sodiumhydroxide, potassium hydroxide and the like achieves deprotection. Atreatment comprising addition of conc. hydrochloric acid and heating,heating in conc. ammonia and the like may be applied.

For example, when R^(P1) is tert-butyldimethylsilyl group, deprotectioncan be achieved by a treatment with tetrabutylammonium fluoride in THFat room temperature, a treatment in the presence of sodium hydroxide inTHF with heating, a treatment with acetic acid-water-THF at roomtemperature or with heating, and the like. In this step, thedeprotection of R^(P1) and hydrolysis of R^(2A) can be performed in twostages.

wherein Hal² is a halogen atom and preferably a fluorine atom or achlorine atom, R^(C3) and R^(C4) are the same or different and each is alower alkyl group such as methyl group, ethyl group and the like, R^(1B)is a “C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituentsselected from halogen atom and group B” defined above, a “C₃₋₁₀ carbonring group optionally substituted by 1 to 5 substituents selected fromgroup A” defined above, a “heterocyclic group optionally substituted by1 to 5 substituents selected from group A” defined above or “—OR^(a4)”defined above, and other symbols are as defined above, wherein thesubstituent R³ is not substituted at the * position.Step 1

Here, Hal¹ is preferably bromine or iodine, and compound [12] can beobtained by conventional halogenation.

For example, compound [11] is reacted with a halogenating agent such asN-bromosuccinimide, N-iodosuccinimide and the like in a solvent such astrifluoromethanesulfonic acid, acetic acid, conc. sulfuric acid, DMF andthe like at room temperature or with heating to give compound [12].

Step 2

An acid halide is obtained by a conventional method by, for example,reacting compound [12] with heating with a halogenating agent such asoxalyl chloride, thionyl chloride and the like, in a solvent such ashydrocarbon solvents (e.g., toluene, xylene etc.); halogenated solvent(e.g., dichloromethane, carbon tetrachloride, 1,2-dichloroethane etc.);ethyl acetate and the like.

Here, for example, when thionyl chloride is used as a halogenatingagent, a catalytic amount of DMF may be added.

Then, compound [13] is added to allow reaction in a solvent in thepresence of a base such as triethylamine, diisopropylethylamine,potassium carbonate, pyridine and the like at room temperature or withheating, after which the resulting compound is reacted with compound[14] at room temperature or with heating to give compound [15].

As the solvent, hydrocarbon solvents such as benzene, toluene, hexane,xylene and the like; halogenated solvents such as dichloromethane,carbon tetrachloride, 1,2-dichloroethane and the like; ether solventssuch as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuranand the like; polar solvents such as acetonitrile and the like, ethylacetate and a mixed solvent thereof can be mentioned.

Step 3

The compound [15] is reacted in the presence of a base such as sodiumcarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide,lithium hydroxide, potassium tert-butoxide, sodium hydride, potassiumhydride and the like, in a solvent to give compound [16].

As one of the preferable production methods, compound [15] may bereacted in the presence of 1,8-diazacyclo[5.4.0]-7-undecene in a solventat room temperature or with heating to give compound [16].

As the solvent, hydrocarbon solvents such as benzene, toluene, hexane,xylene and the like; halogenated solvents such as dichloromethane,carbon tetrachloride, 1,2-dichloroethane and the like; ether solventssuch as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuranand the like; polar solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile and the like and a mixed solvent thereof can bementioned.

Step 4

The compound [16] is reacted with compound [2] in the same manner as inProduction Method 1-1, Step 2 to give compound [I-4].

Step 5

The compound [I-4] is subjected to hydrolysis in the same manner as inProduction Method 1-1, Step 6 to give compound [I-5].Production Method 2-2 Example of Production Method ComprisingIntroduction and Removal of Hydroxyl-Protecting Group

wherein each symbol is as defined above.Step 1

The compound [12] obtained in the same manner as in Production Method2-1, Step 1 is reacted with compound [13] and compound [17] in the samemanner as in Production Method 2-1, Step 2 to give compound [18].

Step 2

A protecting group is introduced into hydroxyl group of compound [18] bya conventional method and then the compound is cyclized in the samemanner as in Production Method 2-1, Step 3 to give compound [19].

Alternatively, compound [18] is cyclized in the same manner as inProduction Method 2-1, Step 3 and then a protecting group is introducedinto hydroxyl group by a conventional method to give compound [19].

For example, when R^(P1) is a tert-butyldimethylsilyl group, compound[18] may be reacted with imidazole and tert-butyldimethylsilyl chloridein a solvent such as DMF and toluene at room temperature.

When R^(P1) is a methoxycarbonyl group, compound [18] may be reactedwith pyridine and methyl chlorocarbonate in a solvent such as chloroformwith cooling or at room temperature.

A similar production method can be use(d for NH₂—R^(1A,) wherein R^(1A,)is a C₁₋₁₀ alkyl group optionally substituted by at least one hydroxylgroup instead of compound [17].

Step 3

The compound [19] is reacted with compound [2] in the same manner as inProduction Method 1-1, Step 2 to give compound [I-6].

Step 4

The compound [I-6] is subjected to hydrolysis by a conventional methodin the same manner as in Production Method 1-2, Step 2 to give compound[I-7]. In this step, the deprotection of R^(P1) and hydrolysis of R^(2A)can be performed in two stages.

wherein R^(a7′) is a C₁₋₁₀ alkyl group optionally substituted by 1 to 3substituents selected from halogen atom and group B, and other symbolsare as defined above.

The fluorine atom on 4-oxoquinoline can be converted to —OR^(a7),—SR^(a7) or —NR^(a7)R^(a8) by a reaction with nucleophilic agent by aconventional method. They can be further converted to —NR^(a7)COR^(a9)or —N═CH—NR^(a10)R^(a11) by a conventional method.

This production method is suitable for introducing a substituent intothe 7-position on 4-oxoquinoline.

Production Method 3-1

An alkoxy group is introduced into compound [21] by a conventionalmethod to give compound [I-8].

For example, compound [I-8] can be obtained by reaction with metalalkoxide with heating in an alcohol solvent such as methanol, ethanol,propanol, butanol and the like, and then hydrolysis.

A solvent and a metal alkoxide need to be determined corresponding to adesired alkoxy group. In the case of a methoxy group, sodium methoxideor potassium methoxide is reacted in methanol, and in the case of anethoxy group, sodium ethoxide or potassium ethoxide is reacted inethanol.

Production Method 3-2

The compound [21] is subjected to amination by a conventional method togive compound [I-9].

For example, compound [I-9] can be obtained by a reaction with an aminein an inactive organic solvent such as THF, dioxane, chloroform,dichloromethane, methanol, ethanol, pyridine and the like with heating.

In addition, compound [I-9] can be also obtained by a reaction with anamine with microwave irradiation in DMF.

Production Method 4

Examples of the production methods of intermediate compound [12] areshown below.

wherein each symbol is as defined above.Step 1

A protecting group is introduced into carboxylic acid of compound [22]by a conventional method to give compound [23].

In the case of esterification, for example, compound [23] can beobtained by a reaction with an alkylating agent such as methyl iodideand the like in a solvent such as DMF, THF, toluene and the like in thepresence of a base such as sodium carbonate, potassium carbonate, sodiumhydride, potassium hydride and the like.

The compound [23] is reduced by a conventional method in the same manneras in Production Method 1-1, Step 3 to give compound [24].

Step 3

The compound [24] is subjected to halogenation by a conventional methodin the same manner as in Production Method 2-1, Step 1 to give compound[25].

Step 4

The compound [25] is subjected to diazotization with sodium nitrite andhydrochloric acid or sulfuric acid in water or an inactive organicsolvent such as THF, dioxane, ethyl acetate, chloroform,dichloromethane, methanol, ethanol, pyridine and the like with coolingor at room temperature, and then subjected to halogenation with cuproushalide such as copper chloride and the like and conc. hydrochloric acidwith cooling or with heating to give compound [26]. Here, Hal² ispreferably a chlorine atom.

Step 5

The hydroxyl group of compound [26] is deprotected by a conventionalmethod to give compound [27].

For example, when R^(P1) is a methyl group, compound [27] can beobtained by reaction with boron tribromide in dichloromethane withcooling.

Step 6

The compound [27] is reacted with compound [8] in the presence of a basein a solvent to give compound [28].

As compound [8], for example, an, alkylating agent such as ethyl iodideand the like can be mentioned.

As the base, potassium carbonate, sodium carbonate, lithium hydride,sodium hydride, potassium hydride and the like can be mentioned, withpreference given to potassium carbonate.

As the solvent, alcohol solvents such as methanol, ethanol, n-propanol,isopropanol and the like; hydrocarbon solvents such as benzene, toluene,hexane, xylene and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and the like; polar solvents suchas dimethylformamide, dimethyl sulfoxide, acetonitrile and the like;water and a mixed solvent thereof can be mentioned.

Step 7

The compound [28] is subjected to hydrolysis by a conventional method inthe same manner as in Production Method 1-1, Step 6 to give compound[12].

Step 8

When R^(P1) in compound [26] is a desired substituent, compound [12′]can be obtained in the same manner as in Step 7.Production Method 5

wherein each symbol is as defined above.Step 1

The compound [29] is subjected to halogenation by a conventional methodin the same manner as in Production Method 2-1, Step. 1 to give compound[30].

Step 2

The compound [30] is reacted with compound [13] and compound [17] in thesame manner as in Production Method 2-1, Step 2 to give compound [31].

Step 3

The compound [31] is reacted in the same manner as in Production Method2-1, Step 3 to give compound [32].

Step 4

The compound [32] is reacted in the same manner as in Production Method2-2, Step 2 to give compound [33].

Step 5

The compound [33] is reacted with compound [2] in the similar as inProduction Method 1-1, Step 2 to give compound [I-10].

Step 6

The compound [I-10] is subjected to hydrolysis in the same manner as inProduction Method 1-2, Step 2 to give compound [I-11].

Step 7

The compound [I-12] can be obtained by introducing an alkoxy group intocompound [I-11] by a conventional method in a similar manner as inProduction Method 3-1.

The 4-oxoquinoline compound represented by the formula [I] of thepresent invention, a pharmaceutically acceptable salt thereof and aproduction method are explained in detail by referring to Examples,which are not to be construed as limitative.

REFERENCE EXAMPLE 1

Preparation of a solution of 2,3-dichlorobenzylzinc chloride in THF

Under an argon stream, to a suspension of zinc powder (55.1 g, 843 mmol)in tetrahydrofuran (THF; 56 ml) was added 1,2-dibromoethane (2.9 ml,33.8 mmol) and the mixture was heated under reflux for 5 min. Then,trimethylsilyl chloride (8.6 ml, 67.5 mmol) was added at 0° C. and themixture was stirred at 0° C. for 5 min, after which a solution of2,3-dichlorobenzyl chloride (82.4 g, 421.7 mmol) in THF (330 ml) wasadded dropwise with ice-cooling. After Completion of the dropwiseaddition, the mixture was warmed to room temperature and stirred for 1hr to give a solution of 2,3-dichlorobenzylzinc chloride in THF.

EXAMPLE 1-1 Synthesis of6-(2,3-dichlorobenzyl)-1,4-dihydro-1-(2-hydroxyethyl)-4-oxo-3-quinolinecarboxylicacid

Step 1 Synthesis of 1,2-dichloro-3-(4-nitrobenzyl)benzene

Under an argon stream, bis(dibenzylideneacetone)palladium (0) (3.2 g,5.6 mmol) and tri(2-furyl)phosphine (2.6 g, 11.2 mmol) were dissolved inTHF (310 ml). To this solution was added dropwise a solution of2,3-dichlorobenzylzinc chloride (421.7 mmol) in THF obtained inReference Example 1 with ice-cooling through a cannula, and then asolution of 4-iodonitrobenzene (70.0 g, 281 mmol) in THF (700 ml) wasadded dropwise. After stirring at room temperature for 2 hrs, saturatedaqueous ammonium chloride solution was added to the reaction solutionand the mixture was filtered through Celite. The filtrate wasconcentrated under reduced pressure. Water was added to the residue andthe mixture was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, and dried over sodium sulfate.After filtration, the filtrate was concentrated under reduced pressureand the solid precipitated during the concentration was collected byfiltration. The filtrate was again concentrated under reduced pressureand the solid precipitated during the concentration was collected byfiltration. The solids obtained by filtration were combined, washed withn-hexane and vacuum-dried to give an object product (60.2 g, yield 76%)as a pale-brown solid.

¹H NMR(CDCl₃ 400 MHz) (δ) ppm: 4.24(2H,s), 7.09(1H,d,J=7.7 Hz),7.18(1H,dd,J=7.8 Hz,7.9 Hz), 7.32(2H,d,J=8.9 Hz), 7.40(1H,d,J=8.0 Hz),8.15(2H,d,J=8.7 Hz)

MS(ESI): M−280Step 2 Synthesis of 4-(2,3-dichlorobenzyl)phenylamine

1,2-Dichloro-3-(4-nitrobenzyl)benzene (25.0 g, 88.6 mmol) obtained inStep 1 was dissolved in acetic acid (400 ml) and zinc powder (70 g, 1.1mol) was added by portions at 0° C. The mixture was stirred at roomtemperature for 1 hr. The reaction mixture was filtered through Celiteand washed with ethanol. The filtrate was concentrated under reducedpressure and the solid precipitated during concentration was collectedby filtration. The solid obtained by the filtration was washed withdiethyl ether, and dissolved in ethyl acetate (500 ml) and water (500ml). A 4N aqueous sodium hydroxide solution was added to neutralize theaqueous layer. The organic layer was separated, and the aqueous layerwas further extracted with ethyl acetate. The organic layers werecombined, washed with water and saturated brine, and dried over sodiumsulfate. After the filtration, the filtrate was concentrated underreduced pressure and the solid precipitated during the concentration wascollected by filtration. The solid obtained by filtration was washedwith n-hexane and vacuum-dried to give an object product (18.1 g, yield81%) as a pale-brown solid.

¹H NMR (CDCl₃ 400 MHz) (δ) ppm: 3.52(2H,brs), 4.01(2H,s),6.63(2H,d,J=8.2 Hz), 6.97(2H,d,J=8.1 Hz), 7.02(1H,d,J=7.6 Hz),7.09(1H,dd,J=7.8 Hz,7.8 Hz), 7.31(1H,d,J=7.8 Hz)

MS(ESI): M+252Step 3 Synthesis of ethyl6-(2,3-dichlorobenzyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate

4-(2,3-Dichlorobenzyl)phenylamine (10.0 g, 39.7 mmol) obtained in Step 2was dissolved in toluene (100 ml) and diethyl ethoxymethylenemalonate(8.8 ml, 43.7 mmol) was added. The mixture was heated under reflux for 3hrs. The reaction solution was concentrated under reduced pressure, anddiphenyl ether (100 ml) was added to dissolve the residue. The mixturewas stirred with heating at 250° C. for 3 hrs. After allowing themixture to cool, n-hexane was added to the reaction solution and theprecipitate was collected by filtration, washed with chloroform andvacuum-dried to give an object product (10.1 g, yield 68%) as apale-yellow solid.

¹H NMR(DMSO-d₆ 400 MHz) (δ) ppm: 1.27(3H,t,J=7.1 Hz), 4.20(2H,q,J=7.1Hz), 4.27(2H,s), 7.34-7.41(2H,m), 7.55-7.57(3H,m), 7.90(1H,s),8.49(1H,d,J=6.6 Hz), 12.26(1H,brs)

MS(ESI): M+376Step 4 Synthesis of ethyl1-(2-acetoxyethyl)-6-(2,3-dichlorobenzyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate

Ethyl 6-(2,3-dichlorobenzyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylateobtained in Step 3 (400 mg, 1.1 mmol) was suspended in dimethylformamide(DMF; 8 ml) and 2-bromoethyl acetate (152 μl, 1.4 mmol) and potassiumcarbonate (440 mg, 3.2 mmol) were added. The mixture was stirred withheating at 80° C. During the stirring, 2-bromoethyl acetate (152 μl, 1.4mmol) was added twice and the mixture was stirred with heating at 80° C.for the total of 1.5 hrs. After allowing the mixture to cool, saturatedaqueous ammonium chloride was added to the reaction solution, and theprecipitate was collected by filtration, washed with water andvacuum-dried to give an object product (468 mg, yield 95%) as a whitesolid.

¹H NMR(DMSO-d₆ 400 MHz) (δ) ppm: 1.25(3H,t,J=9.3 Hz), 1.88(3H,s),4.20(2H,q,J=9.3 Hz), 4.27(2H,s), 4.33-4.41(2H,m), 4.59-4.62(2H,m),7.32-7.41(3H,m), 7.54(1H,dd,J=2.9 Hz,10.2 Hz), 7.64(1H,dd,J=2.4 Hz,11.2Hz), 7.81(1H,d,J=11.7 Hz), 7.88(1H,d,J=2.4 Hz), 8.57(1H,s)Step 5 Synthesis of6-(2,3-dichlorobenzyl)-1,4-dihydro-1-(2-hydroxyethyl)-4-oxo-3-quinolinecarboxylicacid

Ethyl1-(2-acetoxyethyl)-6-(2,3-dichlorobenzyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylateobtained in Step 4 (6.0 g, 13.0 mmol) was suspended in ethanol (480 ml)and 4N aqueous sodium hydroxide solution (84 ml, 21 mmol) was added. Themixture was heated under reflux for 30 min. After allowing the mixtureto cool, the reaction solution was partly concentrated under reducedpressure. Hydrochloric acid was added and the precipitate was collectedby filtration, washed with water and ethanol and vacuum-dried to give anobject product (4.5 g, yield 85%) as a white solid.

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.75(2H, t, J=4.7 Hz), 4.36(2H, s),4.60(2H, t, J=4.8 Hz), 4.98(1H, brs), 7.37-7.39(1H, m), 7.45(1H, dd,J=1.4, 7.6 Hz), 7.57(1H, dd, J=1.5, 8.0 Hz), 7.81(1H, dd, J=2.1, 8.9Hz), 8.02(1H, d, J=8.8 Hz), 8.15(1H, d, J=1.8 Hz), 8.86(1H, s),15.18(1H, brs)

MS (ESI): M+392

m.p.: 247-249° C.

EXAMPLE 1-2 Synthesis of6-(2,3-dichlorobenzyl)-1,4-dihydro-8-fluoro-1-(2-hydroxyethyl)-4-oxo-3-quinolinecarboxylicacid

Step 1 Synthesis of 2,3-difluoro-5-iodobenzoic acid

2,3-Difluorobenzoic acid (5.0 g, 31.6 mmol) was dissolved intrifluoromethanesulfonic acid (25 ml), and N-iodosuccinimide (8.55 g,38.0 mmol) was added by portions at 0° C. under an argon stream. Themixture was stirred at room temperature for 3 hrs., and the reactionsolution was poured into sodium sulfite in ice water. The mixture wasstirred and the precipitate was collected by filtration, washed withwater and vacuum-dried to give an object product (7.5 g, yield 84%) as apale-pink solid.

¹H NMR(CDCl₃ 300 MHz) (δ) ppm: 7.74(1H,m), 8.11(1H,m)

MS(ESI): M−283Step 2 Synthesis of ethyl2-(2,3-difluoro-5-iodobenzoyl)-3-(2-hydroxyethylamino)acrylate

2,3-Difluoro-5-iodobenzoic acid (3.0 g, 10.6 mmol) obtained in Step 1was dissolved in toluene, and thionyl chloride (3.0 ml, 41.1 mmol) andDMF (catalytic amount).were added. The mixture was heated under refluxfor 3 hrs. The reaction solution was concentrated under reduced pressureand THF (15 ml) was added to dissolve the residue. The resultingsolution was added dropwise to a solution of ethyl3-dimethylaminoacrylate (1.66 g, 11.6 mmol) and triethylamine (1.77 ml,12.7 mmol) in THF (10 ml) and the mixture was stirred with heating at50° C. for 2.5 hrs. After allowing the mixture to cool, the reactionmixture was filtered and washed with THF (10 ml). Aminoethanol (0.77 ml,12.7 mmol) was added to the filtrate and the mixture was stirred withheating at 40° C. for 1 hr. After allowing the mixture to cool, waterwas added to the reaction solution and the mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel chromatography (ethyl acetate:hexane=2:1) to givean object product (3.8 g, yield 85%). of a mixture of E form and Z formas a yellow solid.

1H NMR(CDCl₃ 400 MHz) (δ) ppm: 0.91-1.09(3H,m), 1.80-1.89(1H,m),3.52-3.63(2H,m), 3.83-3.91(2H,m), 3.98-4.09(2H,m), 7.36-7.52(2H,m),8.15(1H,d,J=14.4 Hz), 9.6(0.22H,brs), 11.0(0.78H,brs)

MS(ESI): M+426Step 3 Synthesis of ethyl2-(2,3-difluoro-5-iodobenzoyl)-3-┌2-(tert-butyldimethylsilyloxy)ethylamino┘acrylate

Ethyl 2-(2,3-difluoro-5-iodobenzoyl)-3-(2-hydroxyethylamino)acrylate(2.0 g, 4.7 mmol) obtained in Step 2 was dissolved in DMF (10 ml),imidazole (705 mg, 10.4 mmol) and tert-butyldimethylsilyl chloride (1.49g, 9.9 mmol) were added, and stirred at room temperature for 4 hrs.Water was added to the reaction solution and the mixture was extractedwith ethyl acetate. The organic layer was washed with water andsaturated brine, and dried over sodium sulfate. After filtration, thefiltrate was concentrated under reduced pressure, and the obtainedresidue was purified by silica gel chromatography (ethylacetate:hexane=1:4) to give an object product (2.3 g, yield 91%) as awhite solid.

¹H NMR(CDCl₃ 300 MHz) (δ) ppm: 0.07(6H,s), 0.90(9H,s), 1.07(3H,t,J=7.1Hz), 3.45-3.55(2H,m), 3.70-3.80(2H,m), 4.04(2H,q,J=7.1 Hz),7.30-7.50(2H,m), 8.14(1H,d,J=14.1 Hz), 10.80-1.10(1H,m)

MS(ESI): M+540Step 4 Synthesis of ethyl1,4-dihydro-8-fluoro-6-iodo-1-[2-(tert-butyldimethylsilyloxy)ethyl]-4-oxo-3-quinolinecarboxylate

Ethyl2-(2,3-difluoro-5-iodobenzoyl)-3-[2-(tert-butyldimethylsilyloxy)ethylamino]acrylate(2.3 g, 4.3 mmol) obtained in Step 3 was dissolved in THF (25 ml) andsodium hydride (256 mg, 6.4 mmol) was added with ice-cooling. Themixture was stirred at 0° C. for 1 hr. 1N Hydrochloric acid (6.4 ml, 6.4mmol) was added to neutralize the reaction solution. Water was furtheradded and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and saturated brine, and dried over sodiumsulfite. After filtration, the filtrate was concentrated under reducedpressure, and the obtained residue was purified by silica gelchromatography (ethyl acetate:hexane=1:2 to ethyl acetate:hexane=2:1) togive an object product (2.0 g, yield 92%) as a white solid.

¹H NMR(CDCl₃ 300 MHz) (δ) ppm: −0.12(6H,s), 0.79(9H,s), 1.38(3H,t,J=7.1Hz), 3.90-4.00(2H,m), 4.37(2H,q,J=7.1 Hz), 4.40-4.50(2H,m),7.69(1H,dd,J=2.0 Hz,13.7 Hz), 8.40(1H,s), 8.69(1H,d,J=2.0 Hz)

MS(ESI): M+520Step 5 Synthesis of ethyl6-(2,3-dichlorobenzyl)-1,4-dihydro-8-fluoro-1-[2-(tert-butyldimethylsilyloxy)ethyl]-4-oxo-3-quinolinecarboxylate

Under an argon stream, 1M solution (2.9 ml, 2.9 mmol) of2,3-dichlorobenzylzinc chloride in THF obtained in the same manner as inReference Example 1 was added to THF (20 ml), and thenbis(dibenzylideneacetone)palladium(0) (22 mg, 0.039 mmol),tri(2-furyl)phosphine (18 mg, 0.077 mmol) and ethyl1,4-dihydro-8-fluoro-6-iodo-1-[2-(tert-butyldimethylsilyloxy)ethyl]-4-oxo-3-quinolinecarboxylate(1.0 g, 1.9 mmol) obtained in Step 4 were added. The mixture was stirredat room temperature for 17 hrs, and then a solution (1.0 ml, 1.0 mmol)of 2,3-dichlorobenzylzinc chloride in THF was added. The mixture washeated under reflux for 1 hr. After allowing the mixture to cool,saturated aqueous ammonium chloride solution was added to the reactionsolution and insoluble materials were filtered off with Celite. Thefiltrate was extracted with ethyl acetate, and the organic layer waswashed with water and saturated brine, and dried over sodium sulfate.After filtration, the filtrate was concentrated under reduced pressure,and the obtained residue was purified by silica gel chromatography(ethyl acetate:hexane=1:1), and then by PTLC (ethylacetate:chloroform=1:2) to give an object product (562 mg, yield 53%) asa pale-yellow oil.

¹H NMR(CDCl₃ 300 MHz) (δ), ppm: −0.13(6H,s), 0.79(9H,s), 1.38(3H,t,J=7.1Hz), 3.90-4.00(2H,m), 4.23(2H,s), 4.37(2H,q,J=7.1 Hz), 4.40-4.50(2H,m),7.10-7.50(4H,m), 8.20-8.30(1H,m), 8.39(1H,s)

MS (ESI): M+552Step 6 Synthesis of ethyl6-(2,3-dichlorobenzyl)-1,4-dihydro-8-fluoro-1-(2-hydroxyethyl)-4-oxo-3-quinolinecarboxylate

Ethyl6-(2,3-dichlorobenzyl)-1,4-dihydro-8-fluoro-1-[2-(tert-butyldimethylsilyloxy)ethyl]-4-oxo-3-quinolinecarboxylate(350 mg, 0.63 mmol) obtained in Step 5 was dissolved in THF (25 ml) andtetrabutylammonium fluoride (1M THF solution; 1.9 ml, 1.9 mmol) wasadded. The mixture was stirred at room temperature for 1 hr. Water wasadded to the reaction solution and the precipitate was collected byfiltration, washed with water and vacuum-dried to give an object product(279 mg, yield quant) as a pale-yellow solid.

¹H NMR(DMSO-d₆ 300 MHz) (δ) ppm: 1.27(3H,t,J=7.1 Hz), 3.65-3.80(2H,m),4.21(2H,q,J=7.1 Hz), 4.40-4.50(2H,m), 4.99(1H,m), 7.30-7.90(5H,m),8.47(1H,s)

MS(ESI): M+438Step 7 Synthesis of6-(2,3-dichlorobenzyl)-1,4-dihydro-8-fluoro-1-(2-hydroxyethyl)-4-oxo-3-quinolinecarboxylicacid

Ethyl6-(2,3-dichlorobenzyl)-1,4-dihydro-8-fluoro-1-(2-hydroxyethyl)-4-oxo-3-quinolinecarboxylate(80 mg, 0.18 mmol) obtained in Step 6 was dissolved in a mixture ofethanol (2 ml) and THF (1 ml), and 1N aqueous sodium hydroxide solution(1 ml, 1.0 mmol) was added. The mixture was stirred with heating at 60°C. for 1 hr. After allowing the mixture to cool, 10% aqueous citric acidsolution was added to the reaction solution. The precipitate wascollected by filtration, washed with 30% aqueous ethanol andvacuum-dried to give an object product (70 mg, yield 93%) as a whitesolid.

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.78 (2H, m), 4.35 (2H, s), 4.64 (2H,m), 5.00 (1H, m), 7.39 (2H, m), 7.47 (1H, m), 7.58 (1H, m), 8.00 (1H,m), 8.81 (1H, s), 14.80 (1H, s).

MS (ESI): M+409

EXAMPLE 3-38

Step 1

2-Chloro-3-nitrobenzoic acid (6.00 g, 29.77 mmol) was dissolved intrifluoromethanesulfonic acid (40 ml) and N-iodosuccinimide (7.37 g,32.76 mmol) was added by portions at 0° C. The mixture was stirred at40° C. for 4 hrs and the reaction solution was added to ice water. Afterstirring, the precipitate was collected by filtration, washed with waterand vacuum-dried. The obtained solid was dissolved in methanol (50 ml),conc. sulfuric acid (catalytic amount) was added, and the mixture washeated under reflux for 5.5 hrs. The reaction solution was concentratedunder reduced pressure and the obtained residue was purified by silicagel chromatography (ethyl acetate:hexane=1:4) to give an object product(5.35 g, yield 53%) as a pale-yellow solid.

1H NMR(CDCl₃ 300 MHz) (δ) ppm: 3.98(3H, s), 8.11 (1H, d, J=2.1 Hz), 8.24(1H, d, J=2.1 Hz)Step 2

The compound (5.35 g, 15.67 mmol) obtained in Step 1 was dissolved inmethanol (25 ml) and 4N aqueous potassium hydroxide solution (10.00 ml,4.00 mmol) was added. The mixture was heated under reflux for 30 min.After allowing the mixture to cool, 1N hydrochloric acid was added tothe reaction solution and the precipitated solid was collected byfiltration and vacuum-dried to give an object product (4.99 g, yield97%) as a white solid.

¹H NMR(CDCl₃ 300 MHz) (δ) ppm: 8.14 (1H, d, J=2.0 Hz), 8.39 (1H, d,J=2.1 Hz)Step 3

The compound (4.99 g, 15.24 mmol) obtained in Step 2 was dissolved intoluene (50 ml), and thionyl chloride (5.00 ml, 68.54 mmol) anddimethylformamide (catalytic amount) were added. The mixture was heatedunder reflux for 1 hr. The s reaction solution was concentrated underreduced pressure and tetrahydrofuran (80 ml) was added to dissolve theresidue. The resulting solution was added dropwise to a solution ofethyl 3,3-dimethylaminoacrylate. (2.29 g, 16.00 mmol) and triethylamine(2.55 ml, 18.30 mmol) in tetrahydrofuran (50 ml) and the mixture wasstirred with heating at 50° C. for 10 hrs. After allowing the mixture tocool, aminoethanol (1.10 ml, 18.23 mmol) was added to the reactionmixture and the mixture was stirred with heating at 40° C. for 1.5 hrs.After allowing the mixture to cool, water was added to the reactionmixture and the mixture was extracted with ethyl acetate. The organiclayer was washed successively with water and saturated brine, and driedover sodium sulfate. After filtration, the filtrate was concentratedunder reduced pressure, and the obtained residue was purified by silicagel chromatography (ethyl acetate:hexane=2:1) to give an object product(5.35 g, yield 75%) of a mixture of E form and Z form as a yellow solid.

¹H NMR(CDCl₃ 300MHz) (δ) ppm: 0.82-1.01 (3H, m), 3.63 (2H, br),3.85-4.06 (4H, m), 7.65-7.68 (1H, m), 8.02-8.06 (1H, m), 8.21-8.36 (1H,m), 9.78 (0.16H, br), 11.15 (0.84H, br)Step 4

The compound (5.35 g, 11.42 mmol) obtained in Step 3 was dissolved indimethylformamide (50 ml), and imidazole (1.71 g, 25.12 mmol) andtert-butyldimethylsilyl chloride (3.62 g, 24.02 mmol) were added. Themixture was stirred at room temperature for 30 min. Water was added tothe reaction mixture and the mixture was extracted with ethyl acetate.The organic layer was washed successively with water and saturatedbrine, and dried over sodium sulfate. After filtration, concentrationunder reduced pressure gave a crude product (7.10 g) as a pale-yellowsolid.Step 5

The crude product (7.10 g) obtained in Step 4 was dissolved intetrahydrofuran (70 ml) and sodium hydride (731 mg, 18.27 mmol) wasadded with ice-cooling. The mixture was stirred at 0° C. for 45 min. 1NHydrochloric acid (18.3 ml) and water were added to the reactionsolution and stirred, after which the mixture was extracted with ethylAcetate. The organic layer was washed successively with water andsaturated brine, and dried over sodium sulfate. After filtration, thefiltrate was concentrated under reduced pressure and purified by silicagel chromatography (ethyl acetate:hexane=1:4 to 1:2) to give an objectproduct (5.58 g, yield 84%) as a yellow solid.

¹H NMR(CDCl₃ 300 MHz) (δ) ppm: −0.14 (6H, s), 0.73 (9H, s), 1.39 (3H, t,J=7.1 Hz), 3.74 (2H, t, J=4.6 Hz), 4.02 (2H, t, J=4.6 Hz), 4.39 (2H, q,J=7.1 Hz), 8.13 (1H, d, J=2.2 Hz), 8.50 (1H, s), 9.02 (1H, d, J=2.2 Hz)Step 6

The compound (5.00 g, 9.15 mmol) obtained in Step 5 was dissolved intetrahydrofuran (100 ml) and bis(dibenzylideneacetone)palladium(0) (105mg, 0.18 mmol) and tri(2-furyl)phosphine (85 mg, 0.37 mmol) were addedunder an argon stream. A solution of 3-chloro-2-fluorobenzylzinc bromide(11.90 mmol) in tetrahydrofuran prepared as mentioned in Example 4-32,Step 4 was added dropwise at 60° C. After completion of the addition,the mixture was heated under reflux for 4 hrs. After allowing themixture to cool, saturated aqueous ammonium chloride solution was addedto the reaction solution and insoluble material was filtered off withCelite. The filtrate was extracted with ethyl acetate, and the organiclayer was washed successively with water and saturated brine and driedover sodium sulfate. After filtration, the filtrate was concentratedunder reduced pressure, and the obtained residue was purified by silicagel chromatography (ethyl acetate:hexane=1:2 to 1:1) to give an objectproduct (2.67 g, yield 52%) as a brown oil.

¹H NMR(CDCl₃ 300 MHz) (δ) ppm: −0.19 (6H, s), 0.70(9H, s), 1.39 (3H, t,J=7.1 Hz), 3.73 (2H, t, J=4.6 Hz), 4.03 (2H, t, J=4.6 Hz), 4.14 (2H, s),4.38 (2H, q, J=7.1 Hz), 7.02-7.14 (2H, m), 7.29-7.35 (1H, m), 7.73 (1H,d, J=2.2 Hz), 8.50 (1H, s), 8.59 (1H, s)Step 7

The compound (1.00 g, 1.79 mmol) obtained in Step 6 was dissolved inacetic acid (20 ml) and zinc powder (1.16 g, 17.76 mmol) was added. Themixture was stirred at room temperature for 4 hrs. The reaction mixturewas filtered through Celite and saturated aqueous sodium hydrogencarbonate was added to the filtrate. The mixture was extracted withethyl acetate. The organic layer was washed successively with saturatedaqueous sodium hydrogen carbonate, water and saturated brine, and driedover sodium sulfate. After filtration, the filtrate was concentratedunder reduced pressure, and the obtained residue was purified by silicagel chromatography (ethyl acetate). To the residue obtained was addedethyl ether and the mixture was sonicated. After filtration, it wasvacuum-dried to give an object product (730 mg, yield 77%) as apale-orange solid.

¹H NMR(CDCl₃ 300 MHz) (δ) ppm: −0.06 (6H, s), 0.77(9H, s), 1.41(3H, t,J=7.1 Hz), 4.01 (2H, s), 4.08 (2H, t, J=4.7 Hz), 4.39 (2H, q, J=7.1 Hz),4.50 (2H, brs), 4.75 (2H, t, J=4.7 Hz), 6.81 (1H, s), 6.94-7.08 (2H, m),7.20-7.26 (1H, m), 7.91 (1H, s), 8.34 (1H, s)Step 8

The compound (100 mg, 0.19 mmol) obtained in Step 7 was dissolved indimethylformamide (2 ml), and methyl iodide (0.029 ml, 0.47 mmol) andsodium hydride (23 mg, 0.56 mmol) were added. The mixture was stirred atroom temperature for 2 hrs. A 10% aqueous citric acid solution was addedto the reaction mixture, and the mixture was stirred and extracted withethyl acetate. The organic layer was washed successively with water andsaturated brine, and dried over sodium sulfate. After filtration, thefiltrate was concentrated under reduced pressure and subjected to silicagel chromatography (ethyl acetate:hexane=2:1) to give a crudely purifiedproduct (45 mg) as a pale-red solid.

¹H NMR(CDCl₃ 300 MHz) (δ) ppm: −0.33-−0.29 (6H, m), 0.64-0.69 (9H, m),1.23-1.41(3H, m), 2.66-2.70 (6H, m), 3.55-3.59 (2H, m), 4.36-4.4.2 (4H,m), 4.82-4.96 (2H, m), 6.96-7.11 (2H, m), 7.23-7.30(2H, m), 8.16-8.15(1H, m), 8.40-8.66 (1H, m)Step 9

The crudely purified product (45 mg) obtained in Step 8 was dissolved intetrahydrofuran (1 ml), and 1M solution of tetrabutylammonium fluoride(1.00 ml, 1.00 mmol) in THF was added. The mixture was stirred at roomtemperature for 5 min. To the reaction solution were added ethanol (1ml) and 1N aqueous sodium hydroxide solution (1 ml, 1.00 mmol), and themixture was heated under reflux for 2 hrs. After allowing the mixture tocool, 10% aqueous citric acid solution was added to the reactionsolution. The mixture was stirred and extracted twice with chloroform.The organic layer was washed with saturated brine, and dried over sodiumsulfate. After filtration, the filtrate was concentrated under reducedpressure and subjected to silica gel chromatography(chloroform:methanol:acetic acid=10:1:0.1) to give a crudely purifiedproduct. To the crudely purified product was added aqueous ethanol andthe mixture was sonicated. After filtration, the filtrate wasvacuum-dried to give an object product (22 mg, yield 27%) as a beigesolid.

¹H NMR(DMSO-d₆ 300 MHz) (δ) ppm: 2.67 (6H, s), 3.39 (2H, m), 4.21 (2H,s), 4.72 (1H, t), 4.97 (2H, t), 7.20-7.22 (1H, m), 7.40-7.50 (2H, m),7.65 (1H, s), 7.84 (1H, s), 15.10 (1H, s)

MS(ESI): M+419

EXAMPLE 3-62

Step 1

2,4-Difluoro-5-iodobenzoic acid (3.00 g, 10.60 mmol) obtained in Example4-33, Step 1 was dissolved in toluene (10 ml), and thionyl chloride(3.00 ml, 41.10 mmol) and dimethylformamide (catalytic amount) wereadded. The mixture was heated under reflux for 1.5 hrs. The reactionsolution was concentrated under reduced pressure and tetrahydrofuran (15ml) was added to dissolve the residue. The resulting solution was addeddropwise to a solution of ethyl 3,3-dimethylaminoacrylate (1.66 g, 11.60mmol) and triethylamine (1.77 ml, 12.70 mmol) in tetrahydrofuran (10ml), and the mixture was stirred with heating at 50° C. for 2.5 hrs.After, allowing the mixture to cool, the reaction mixture was filteredand washed with tetrahydrofuran (10 ml). To the filtrate was addedaminoethanol (0.77 ml, 12.76 mmol) and the mixture was stirred withheating at 40° C. for 1 hr. After allowing the mixture to cool, waterwas added to the reaction solution and the mixture was extracted withethyl acetate. The organic layer was washed successively with water andsaturated brine, and dried over sodium sulfate. After filtration, thefiltrate was concentrated under reduced pressure, and the obtainedresidue was purified by silica gel chromatography (ethylacetate:hexane=2:1) to give a crudely purified product (3.00 g, yield67%) of a mixture of E form and Z form as a yellow solid.Step 2

The compound (3.00 g, 7.06 mmol) obtained in Step 1 was dissolved indimethylformamide (15 ml) and imidazole (1.06 g, 15.52 mmol) andtert-butyldimethylsilyl chloride (2.23 g, 14.82 mmol) were added. Themixture was stirred at room temperature for 14 hrs. Water was added tothe reaction mixture and the mixture was extracted with ethyl acetate.The organic layer was washed successively with water and saturatedbrine, and dried over sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel chromatography (ethyl acetate:hexane=1.:4) togive an object product (3.22 g, yield 85%) as a white solid.

¹H NMR(CDCl₃ 300 MHz) (δ) ppm: 0.06 (6H, s), 0.90 (9H, s), 1.08 (3H, t,J=7.1 Hz), 3.51 (2H, br), 3.79(2H, t, J=4.9 Hz), 4.05(2H, q, J=7.1 Hz),6.78 (1H, dd, J=7.9, 9.4 Hz), 7.71 (1H, dd, J=7.3, 7.3 Hz), 8.11 (1H, d,J=14.0 Hz), 10.91 (1H, br)Step 3

The compound (3.22 g, 5.97 mmol) obtained in Step 2 was dissolved intetrahydrofuran (35 ml) and sodium hydride (358 mg, 8.95 mmol) was addedwith ice-cooling. The mixture was stirred at 0° C. for 2.5 hrs. 1NHydrochloric acid (8.90 ml, 8.90 mmol) and water (35 ml) were added tothe reaction mixture and the mixture was stirred. The precipitate wascollected by filtration, and purified by silica gel chromatography(ethyl acetate:hexane=1:2 to 2:1) to give an object product (2.52 g,yield 81%) as a pale-yellow solid.

¹H NMR(CDCl₃ 300 MHz) (δ) ppm: −0.11(6H, s), 0.79 (9H, s), 1.39 (3H, t,J=7.1 Hz), 3.96 (2H, t, J=4.8 Hz), 4.23(2H, t, J=4.8 Hz), 4.38(2H, q,J=7.1 Hz), 7.14 (1H, d, J=9.3 Hz), 8.47 (1H, s), 8.93 (1H, d, J=7.2 Hz)Step 4

The compound (1.00 g, 1.93 mmol) obtained in Step 3 was dissolved intetrahydrofuran (20 ml). Under an argon stream,bis(dibenzylideneacetone)palladium(0) (22 mg, 0.039 mmol) andtri(2-furyl)phosphine (18 mg, 0.077 mmol) were added. To this mixturewas added a solution of 3-chloro-2-fluorobenzylzinc bromide (2.89 mmol)in tetrahydrofuran prepared as mentioned above dropwise at 60° C. Aftercompletion of the addition, the mixture was heated under reflux for 1hr. After allowing the mixture to cool, saturated aqueous ammoniumchloride solution was added to the reaction solution. Insoluble materialwas filtered off with Celite. The filtrate was extracted with ethylacetate, and the organic layer was washed successively with water andsaturated brine, and dried over sodium sulfate. After filtration, thefiltrate was concentrated under reduced pressure, and the obtainedresidue was purified by silica gel chromatography (ethylacetate:hexane=2:1) to give an object product (573 mg, yield 55%) as apale-yellow solid.

¹H NMR(CDCl₃ 300 MHz) (δ) ppm: −0.12(6H, s), 0.78 (9H, s), 1.38 (3H, t,J=7.1 Hz), 3.99 (2H, t), 4.13(2H, s), 4.23 (2H, t), 4.37 (2H, q, J=7.1Hz), 6.96-7.13 (3H, m), 7.25-7.31(1H, m), 8.39 (1H, d), 8.46 (1H, s)Step 5

The compound (170 mg, 0.32 mmol) obtained in Step 4 was dissolved intetrahydrofuran (1 ml) and 2N aqueous sodium hydroxide solution (4.00ml, 2.00 mmol) was added. The mixture was heated under reflux for 3.5hrs. After allowing the mixture to cool, 10% aqueous citric acidsolution was added to the reaction solution, and the precipitate wascollected by filtration, washed with 50% aqueous ethanol andvacuum-dried to give an object product (117 mg, yield 94%) as a whitesolid.

¹H NMR(DMSO-d₆ 300 MHz) (δ) ppm: 3.73(2H, br), 4.25 (2H, s), 4.58(2H,br), 4.96(1H, br), 7.19-7.22 (1H, m), 7.30-7.36 (1H, m), 7.49-7.54 (1H,m), 8.03 (1H, d), 8.30 (1H, d), 8.88(1H, s), 15.42 (1H, brs)Step 6

The compound (65 mg, 0.17 mmol) obtained in Step 5 was dissolved indimethyl sulfoxide (2.5ml) and microwave was irradiated thereon at 50 Wand 120° C. or below for 20 min. After allowing the mixture to cool, 10%aqueous citric acid solution was added to the reaction mixture, and theprecipitate was collected by filtration, washed with water andvacuum-dried to give an object product (66 mg, yield 96%) as a whitesolid.

¹H NMR(DMSO-d₆ 300 MHz) (δ) ppm: 2.88 (6H, s), 3.70-3.80 (2H, m),4.22(2H, s), 4.60-4.70 (2H, m), 5.05 (1H, t), 7.20-7.31 (3H, m),7.50-7.60 (1H, m), 7.80 (1H, s), 8.78 (1H, s), 15.30-15.40(1H, brs)

MS(ESI): M+419

EXAMPLE 3-73

Step 1

2,4-Difluoro-5-iodobenzoic acid (5.00 g, 17.60 mol) was dissolved intoluene (25 ml), and oxalyl chloride (2.00 ml, 22.93 mmol) anddimethylformamide (catalytic amount) were added. The mixture was stirredat room temperature for 12 hrs. After filtering the reaction solution,the filtrate was concentrated under reduced pressure and toluene (20 ml)was added. Insoluble material was filtered with Celite. The filtrate wasconcentrated under reduced pressure and tetrahydrofuran (20 ml) wasadded to dissolve the obtained residue. The resulting solution was addeddropwise to a solution of ethyl 3,3-dimethylaminoacrylate (3.28 g, 22.91mmol) and triethylamine (3.70 ml, 26.55 mmol) in tetrahydrofuran (20ml). The mixture was heated under reflux for 1 hr. After allowing themixture to cool, water and ethyl acetate (50 ml) were added to thereaction mixture. The mixture was stirred and partitioned. The organiclayer was washed successively with 1N hydrochloric acid (20 ml) andwater (200 ml), and dried over sodium sulfate. After filtration, thefiltrate was concentrated under reduced pressure to give a crude product(7.24 g) as a brown oil.Step 2

The crude product (7.24 g) obtained in Step 1 was dissolved intetrahydrofuran (20 ml) and (S)-2-amino-1-butanol (1.89 g, 21.24 mmol)was added. The mixture was stirred with heating at 60° C. for 1.5 hrs.After allowing the mixture to cool, the reaction solution wasconcentrated under reduced pressure and the obtained residue wasdissolved in dimethylformamide (20 ml). Potassium carbonate (7.33 g,53.02 mmol) was added and the mixture was stirred with heating at 70° C.for 1 hr. After allowing the mixture to cool, the reaction mixture wasconcentrated under reduced pressure. Water (150 ml) was added to theresidue and the mixture was stirred at room temperature for 30 min. Theprecipitate was collected by filtration. The obtained solid was washedwith water (50 ml), and then with a mixture (50 ml) of hexane:diethylether=7:3, and vacuum-dried to give an object product (4.69 g, yield61%) as a white solid.

¹H NMR(CDCl₃ 300 MHz) (δ) ppm: 0.97(3H, t, J=7.4 Hz), 1.40(3H, t, J=7.1Hz), 1.95-2.05 (1H, m), 2.11-2.21 (1H, m), 4.05 (1H, br), 4.34-4.39 (5H,m), 5.59 (1H, br), 7.30 (1H, d, J=10.0 Hz), 8.04 (1H, d, J=7.1 Hz), 8.58(1H, s)Step 3

The compound (4.69 g, 10.82 mmol) obtained in Step 2 was dissolved indimethylformamide (20 ml), and imidazole (950 mg, 13.95 mmol) andtert-butyldimethylsilyl chloride (1.95 g, 12.96 mmol) were added. Themixture was stirred at room temperature for 14.5 hrs. Water was added tothe reaction mixture and the mixture was extracted with ethyl acetate(50 ml). The organic layer was washed 3 times with water and then withsaturated brine, and dried over sodium sulfate. After filtration, thefiltrate was concentrated under reduced pressure, and the obtainedresidue was purified by silica gel chromatography (ethylacetate:hexane=3:7) to give an object product (5.06 g, yield 86%) as ayellow oil.

¹H NMR(CDCl₃ 300 MHz) (δ) ppm: −0.08 (3H, s), −0.05 (3H, s), 0.77 (9H,s), 0.98 (3H, t, J=7.5 Hz), 1.40 (3H, t, J=7.2 Hz), 1.94-2.10(2H, m),3.90 (2H, br), 4.35-4.43(3H, m), 7.26 (1H, d, J=9.9 Hz), 8.59 (1H, s),8.95 (1H, d, J=7.2 Hz)Step 4

The compound (5.06 g, 9.24 mmol) obtained in Step 3 was dissolved intetrahydrofuran (20 ml), and bis(dibenzylideneacetone)palladium(0) (266mg, 0.46 mmol) and tri(2-furyl)phosphine (215 mg, 0.92 mmol) were addedunder an argon stream. A solution of 3-chloro-2-fluorobenzylzinc bromide(18.50 mmol) in tetrahydrofuran prepared as mentioned above was addeddropwise. After completion of the addition, the mixture was stirred withheating at 60° C. for 1 hr. After allowing the mixture to cool, waterand ethyl acetate were added to the reaction solution and the mixturewas stirred and partitioned. The organic layer was washed successivelywith 1N hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate and saturated brine, and dried over sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure and theresidue was purified by silica gel chromatography (ethylacetate:hexane=1:1 to 2:1) to give an object product (3.86 g, yield 74%)as a brown oil.

¹H NMR(CDCl₃ 300 MHz) (δ) ppm: −0.10(3H, s), −0.06(3H, s), 0.752(9H, s),0.98(3H, t, J=7.4 Hz), 1.403H, t, J=7.1 Hz), 1.90-2.12(2H, m), 3.89 (2H,br), 4.12 (2H, s), 4.35-4.49(3H, m), 6.97-7.08 (2H, m), 7.22-7.29 (2H,m), 8.40 (1H, d, J=8.7 Hz), 8.58(1H, s)Step 5

To the compound (3.86 g, 6.85 mmol) obtained in Step 4 were added 28%sodium methoxide in methanol (40.00 ml, 0.20 mol) and water (2.00 ml,0.11 mol), and the mixture was heated under reflux for 5.5 hrs. Afterallowing the mixture to cool, the reaction solution was concentratedunder reduced pressure and 6N hydrochloric acid was added to theobtained residue. The mixture was stirred, and extracted twice withethyl acetate. The organic layer was washed successively with water andsaturated brine, dried over magnesium sulfate, filtered and concentratedunder reduced pressure. The obtained residue was recrystallized fromethanol (200 ml) to give an object product (2.03 g, yield 68%) as awhite solid.

¹H NMR(DMSO-d₆ 300 MHz) (δ) ppm: 0.87 (3H, t, J=7.3 Hz), 1.80-2.10 (2H,m), 3.70-3.90 (2H, m), 4.02 (3H, s), 4.11 (2H, s), 5.00-5.19 (2H, m),7.16-7.24 (2H, m), 7.44-7.48 (2H, m), 8.04 (1H, s), 8.78 (1H, s), 15.44(1H, s)

MS(ESI): M+434

EXAMPLE 3-75

Step 1

2-Fluoro-5-iodobenzoic acid (6.60 g, 24.81 mmol) was dissolved inchloroform (70 ml) and-oxalyl chloride (4.30 ml, 49.29 mmol) anddimethylformamide (catalytic amount) were added. The mixture was stirredat room temperature for 3 hrs. The reaction solution was concentratedunder reduced pressure and chloroform (35 ml), was added to dissolve theresidue. The obtained solution was added dropwise to a solution of ethyl3,3-dimethylaminoacrylate (4.26 g, 29.75 mmol) and triethylamine (5.19ml, 37.24 mmol) in chloroform (35 ml), and the mixture was stirred-atroom temperature for 15 hrs. Water was added to partition the reactionsolution, and the organic layer was washed with saturated brine anddried over sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure and the obtained residue waspurified by silica gel chromatography (ethyl acetate:hexane=1:2 to 1:1)to give an object product (6.40 g, yield 66%) f a mixture of E form andZ form as an orange solid.

¹H NMR(CDCl₃ 400 MHz) (δ) ppm: 0.94 (3H, t, J=47.2 Hz), 2.88 (3H, brs),3.31 (3H, brs), 3.97 (2H, q), 6.78 (1H, dd, J=8.4, 10.0 Hz), 7.65-7.67(1H, m), 7.78(1H, s), 7.85 (1H, brs)

MS(ESI): M+392Step 2

The compound (300 mg, 0.77 mmol) obtained in Step 1 was dissolved intetrahydrofuran (1.5 ml) and (S)-(+)-tert-leucinol (0.12 ml, 0.92 mmol)was added. The mixture was stirred with heating at 60° C. for 1 hr. Thereaction solution was concentrated under reduced pressure and theobtained residue was dissolved in dimethylformamide (1.2 ml). Potassiumcarbonate (318 mg, 2.30 mmol) was added and the mixture was stirred withheating at 70° C. for 5.5 hrs. After cooling, 1N hydrochloric acid (5ml) was added to the reaction mixture and the mixture was stirred withice-cooling for 30 min. The precipitate was collected by filtration andthe obtained solid was washed with 30% aqueous ethanol (6 ml), and thenwith a mixture (5 ml) of hexane:diethyl ether=2:1 and vacuum-dried togive an object product (276 mg, yield 81%) as a pale-yellow solid.

¹H NMR(CDCl₃ 300 MHz) (δ) ppm: 0. 98 (9H, s), 1.41 (3H, t, J=7.0 Hz),4.25-4.41 (4H, m), 4.64-4.70(1H, m), 5.14 (1H, br), 7.46 (1H, d, J=9.0Hz), 7.89(1H, dd, J=2.2, 9.1 Hz), 8.06 (1H, d, J=2.1 Hz), 8.69(1H, s)Step 3

The compound (276 mg, 0.62 mmol) obtained in Step 2 was dissolved indimethylformamide (1 ml) and imidazole (51 mg, 0.75 mmol) andtert-butyldimethylsilyl chloride (122 mg, 0.81 mmol) were added. Themixture was stirred at room temperature for 30 min. Water was added tothe reaction mixture and the mixture was extracted twice with ethylacetate, and the organic layer was washed twice with water and then withsaturated brine, and dried over sodium sulfate. After filtration, thefiltrate was concentrated under reduced pressure, and the obtainedresidue was purified by silica gel chromatography (ethylacetate:hexane=3:5) to give an object product (314 mg, yield 91%) as awhite amorphous form.

¹H NMR(CDCl₃ 300 MHz) (δ) ppm: −0.09 (3H, s), −0.01 (3H, s), 0.66 (9H,s), 1.04 (9H, s), 1.41 (3H, t, J=7.2 Hz), 4.10-4.14 (2H, m), 4.40 (2H,q, J=7.0 Hz), 4.58-4.63 (1H, m), 7.39(1H, d, J=9.3 Hz), 7.89 (1H, dd,J=2.2, 8.8 Hz), 8.67 (1H, s), 8.87 (1H, d, J=2.1 Hz)Step 4

The compound (314 mg, 0.56 mmol) obtained in Step 3 was dissolved intetrahydrofuran (1.2 ml), and bis(dibenzylideneacetone)palladium(0) (16mg, 0.028 mmol) and tri(2-furyl)phosphine (13 mg, 0.056 mmol) were addedunder an argon stream. A solution of 3-chloro-2-fluorobenzylzinc bromide(1.13 mmol) in tetrahydrofuran prepared as mentioned above was addeddropwise. After completion of the addition, the mixture was stirred withheating at 50° C. for 1.5 hrs. After allowing the mixture to cool, waterand ethyl acetate were added to the reaction solution and the mixturewas stirred. Insoluble material was filtered with Celite. The filtratewas partitioned and the organic layer was washed successively with waterand saturated brine, and dried over sodium sulfate. After filtration,the filtrate was concentrated under reduced pressure and the obtainedresidue was purified by silica gel chromatography (ethylacetate:hexane=1:1) to give an object product (283 mg, yield 87%) as abrown amorphous form.

¹H NMR(CDCl₃ 400 MHz) (δ) ppm: −0.11 (3H, s), −0.01 (3H, s), 0.63 (9H,s), 1.06 (9H, s), 1.41 (3H, t, J=7.0 Hz), 4.08-4.16 (4H, m), 4.38 (2H,q, J=7.0 Hz), 4.61-4.67 (1H, m), 6.95-7.08(2H, m), 7.23-7.27(1H, m),7.47-7.49 (1H, m), 7.53-7.55 (1H, m), 8.41 (1H, d, J=2.0 Hz); 8.68 (1H,s)Step 5

The compound (283 mg, 0.49 mmol) obtained in Step 4 was dissolved inethanol (2 ml) and 1N aqueous sodium hydroxide solution (1.00 ml, 1.00mmol) was added. The mixture was heated under reflux for 1 hr. Afterallowing the mixture to cool, acetic acid (0.35 ml) was added to thereaction solution and the mixture was stirred. The precipitate wascollected by filtration and the solid was suspended in diethyl ether (10ml). After filtration, the mixture was vacuum-dried to give an objectproduct (157 mg, yield 74%) as a white solid.

¹H NMR(DMSO-d₆ 400 MHz) (δ) ppm: 1.00 (9H, s), 4.07-4.12 (2H, m), 4.30(2H, ), 5.12-5.14 (2H, m), 7.20-7.25 (1H, m), 7.40-7.45 (1H, m),7.51-7.53 (1H, m), 7.87 (1H, d), 8.25 (1H, s), 8.41 (1H, d, J=9.2 Hz),8.85 (1H, s), 15.20-15.21 (1H, br)

MS(ESI): M+432

EXAMPLE 4-20

Step 1

2-Chloro-4-hydroxybenzoic acid (5.18 g, 30.02 mmol) was dissolved intrifluoromethanesulfonic acid. (25 g) and N-iodosuccinimide (6.75 g,30.00 mmol) was added by portions at 0° C. The mixture was stirred atroom temperature for 15 hrs and trifluoromethanesulfonic acid (25 g) wasfurther added. N-Iodosuccinimide (2.02 g, 8.98 mmol) was added byportions at 0° C. The mixture was stirred at room temperature for 13.5hrs and the reaction mixture was added to ice water (300 ml). Themixture was stirred for 2 hrs. The precipitate was collected byfiltration, washed with water and vacuum-dried to give an object productas a mixture of 2-chloro-4-hydroxy-5-iodobenzoic acid and2-chloro-3,5-diiodo-4-hydroxybenzoic acid (8:2)(5.76 g).Step 2

The mixture (3.89 g) obtained in Step 1 was dissolved indimethylformamide (20 ml) and potassium carbonate (8.97 g, 64.90 mmol)and isopropyl iodide (6.50 ml, 65.15 mmol) were added. The mixture wasstirred with heating at 80° C. for 2.5 hrs. The reaction mixture wasadded to 1N hydrochloric acid (100 ml), and toluene (100 ml) was furtheradded. The mixture was stirred and insoluble material was filteredthrough Celite. The filtrate was partitioned and the organic layer waswashed with water three times, and dried over sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure and theobtained residue was purified by silica gel chromatography (ethylacetate:hexane=1:9) to give an object product as a mixture (4.08 g).Step 3

The mixture (4.08.g) obtained in Step 2 was dissolved in ethanol (20 ml)and 1N aqueous sodium hydroxide solution (20.00 ml, 20.00 mmol) wasadded. The mixture was heated under reflux for 24 hrs. After allowingthe mixture to cool, 1N hydrochloric acid (30 ml) was added to thereaction solution and the mixture was stirred. The mixture was extractedwith ethyl acetate three times. The organic layer was washedsuccessively with water and saturated brine, and dried over sodiumsulfate. After filtration, concentration under reduced pressure gave anobject product as a mixture (3.40 g).Step 4

The mixture (3.40 g) obtained in Step 3 was dissolved in toluene (35 ml)and thionyl chloride (3.40 ml, 46.61 mmol) and dimethylformamide(catalytic amount) were added. The mixture was heated under reflux for1.5 hrs. The reaction solution was concentrated under reduced pressureand tetrahydrofuran (25 ml) was added to dissolve the residue. Theobtained solution was added dropwise to a solution of ethyl3,3-dimethylaminoacrylate (4.29 g, 30.00 mmol) and triethylamine (4.17ml, 30.00 mmol) in tetrahydrofuran (10 ml) and the mixture was heatedunder reflux for 14 hrs. After allowing the mixture to cool, water andethyl acetate were added to the reaction mixture, and the mixture wasstirred and partitioned. The organic layer was washed successively withwater and saturated brine, and dried over sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure, andthe obtained residue was purified by silica gel chromatography (ethylacetate:hexane=1:1.5 to 1.5:1) to give an object product as a mixture(2.71 g).Step 5

The mixture (300 mg) obtained in Step 4 was dissolved in tetrahydrofuran(2 ml), and (S)-(+)-tert leucinol (0.10 ml, 0.77 mmol) was added. Themixture was heated under reflux for 20 min. After allowing the mixtureto cool, the reaction solution was concentrated under reduced pressureand the obtained residue was dissolved in dimethylformamide (4 ml).Imidazole (110 mg, 1.61 mmol) and tert-butyldimethylsilyl chloride (214mg, 1.42 mmol) were added and the mixture was stirred at roomtemperature for 20 min. Water was added to the reaction solution and themixture was extracted with ethyl acetate. The organic layer was washedsuccessively with water and saturated brine, and dried over sodiumsulfate. After filtration, the filtrate was concentrated under reducedpressure, and the obtained residue was purified by silica gelchromatography (ethyl acetate:hexane=1:4) to give an object product as amixture (391 mg).Step 6

The mixture (391 mg) obtained in Step 5 was dissolved in toluene (5 ml)and sodium hydride (29 mg, 0.73 mmol) was added under ice-cooling. Themixture was stirred at room temperature for 30 min and dimethylformamide(3 ml), potassium carbonate (100 mg, 0.72 mmol) and ethyl iodide (0.058ml, 0.73 mmol) were added to the reaction mixture. The mixture wasstirred with heating at 60° C. for 30 min. After allowing the mixture tocool, the reaction-mixture was added to ice water. 1N Hydrochloric acidwas added for neutralization and the mixture was extracted with ethylacetate. The organic layer was washed successively with water andsaturated brine, and dried over sodium sulfate. After filtration, thefiltrate was concentrated under reduced pressure and the obtainedresidue was purified by silica gel chromatography (ethylacetate:hexane=4:5 to 2:1) to give an object product (258 mg, yield 19%)as a pale-white yellow solid.

¹H NMR(CDCl₃ 300 MHz) (δ) ppm: −0.09 (3H, s), 0.00 (3H, s), 0.67 (9H,s), 1.05(9H, s), 1.40 (3H, t, J=7.1 Hz), 1.46 (6H, d, J=6.0 Hz),4.09-4.20(2H, m), 4.39 (2H, q, J=7.1 Hz), 4.43-4.49 (1H, m),4.61-4.69(1H, m), 6.87 (1H, s), 8.60 (1H, s), 8.94(1H, S)Step 7

Ethyl1,4-dihydro-1-{2,2-dimethyl-1-[(tert-butyldimethylsilyloxy)methyl]propyl}-6-iodo-7-isopropyloxy-4-oxo-3-quinolinecarboxylate(258 mg, 0.42 mmol) obtained in Step 6 was dissolved in tetrahydrofuran(5 ml). Under an argon stream, bis(dibenzylideneacetone)palladium(0)(9.7 mg, 0.017 mmol) and tri(2-furyl)phosphine (7.8 mg, 0.034 mmol) wereadded and a solution of 3-chloro-2-fluorobenzylzinc bromide (0.63 mmol)in tetrahydrofuran prepared as mentioned above was added dropwise at 60°C. After completion of the addition, the mixture was heated under refluxfor 1 hr. After allowing the mixture to cool, saturated aqueous ammoniumchloride solution was added to the reaction solution and the mixture wasstirred and filtered through Celite. Water was added to the filtrate andthe mixture was extracted with ethyl acetate. The organic layer waswashed successively with water and saturated brine, and dried oversodium sulfate. After filtration, the filtrate was concentrated underreduced pressure and the obtained residue was crudely purified by silicagel chromatography (ethyl acetate:hexane=1:1 to 2:1) to give a crudelypurified product (216 mg) as a pale-yellow oil.Step 8

The crudely purified product (216 mg) obtained in Step 7 was dissolvedin a mixture of ethanol (2 ml) and tetrahydrofuran (1 ml), and 1Naqueous sodium hydroxide solution (2.00 ml, 2.00 mmol) was added. Themixture was heated under reflux for 1 hr. After allowing the mixture tocool, 10% aqueous citric acid solution was added to the reactionsolution and the mixture was stirred. The mixture was extracted withethyl acetate. The organic layer was washed successively with water andsaturated brine, and dried over sodium sulfate. After filtration, thefiltrate was concentrated under reduced pressure. The residue wastreated with a mixture of diethyl ether and hexane. After filtration,the solid was vacuum-dried to give an object product (140 mg, yield 68%)as a white solid.

¹H NMR(DMSO-d₆ 300 MHz) (δ) ppm: 0.97 (9H, s), 1.18 (3H, d, J=5.9 Hz),1.26 (3H, d, J=6.0 Hz), 4.04-4.09 (4H, m), 5.09-5.13 (3H, m), 7.12-7.21(2H, m), 7.43-7.51 (2H, m), 8.19 (1H, s), 8.78 (1H, s), 15.46 (1H, s)MS(ESI): M+ 490

EXAMPLE 4-32

Step 1

2,4-Difluoro-5-iodobenzoic acid (650.57 g, 2.29 mol) was dissolved intoluene (1300 ml), and thionyl chloride (184 ml, 2.52 mol) anddimethylformamide (catalytic amount) were added The mixture was stirredat 90° C. for 2 hrs. After allowing the mixture to cool, the reactionsolution was concentrated under reduced pressure. The residue wasdissolved in toluene (330 ml) followed by concentration under reducedpressure, and repeated again. The residue was dissolved in toluene (690ml) and the obtained solution was added dropwise to a solution of ethyl3,3-dimethylaminoacrylate (361.52 g, 2.525 mol) anddiisopropylethylamine (480 ml, 2.75 mol) in toluene (690 ml) and themixture was stirred with heating at 90° C. for 3 hrs. After allowing themixture to cool, (S)-(+)-valinol (260.00 g, 2.52 mol) was added to thereaction mixture and the mixture was stirred at room temperature for 1hr. Water (2600 ml) was added to the reaction mixture and the mixturewas partitioned. The aqueous layer was extracted with toluene (680 ml).The organic layers were combined, washed twice with water (2000 ml), anddried over sodium sulfate. After filtration, concentration under reducedpressure gave a crude product (1180 g) as a brown oil.Step 2

The crude product (1180 g) obtained in Step 1 was dissolved indimethylformamide (2500 ml) and finely ground potassium carbonate(292.00 g, 1.06 mol) was added. The mixture was stirred at roomtemperature for 22 hrs. The reaction mixture was added to ice water (ca.10 L) and the mixture was stirred for 30 min. The precipitate wascollected by filtration and washed with water (2000 ml). The obtainedsolid was vacuum-dried, and suspended in ethyl acetate (5000 ml).Filtration and vacuum-drying gave an object product (774.63 g, yield82%) as a white yellow solid.

¹H NMR(DMSO-d₆ 300 MHz) (δ) ppm: 0.72 (3H, d, J=6.6 Hz), 1.10 (3H, d,J=6.6 Hz), 1.28(3H, t, J=7.0 Hz), 2.27 (1H, br), 3.77 (1H, br), 3.86(1H,br), 4.23 (2H, q, J=7.0 Hz), 4.56(1H, br), 5.12 (1H, t, J=4.9 Hz),8.09(1H, d, J=11.1 Hz), 8.62 (1H, d, J=7.5 Hz), 8.68(1H, s)

MS(ESI): M+ 448Step 3

The compound (626.15 g, 1.40 mol) obtained in Step 2 was dissolved inchloroform (1250 ml), and pyridine (433 ml, 5.60 mol) and4-(dimethylamino)pyridine (17.10 g, 0.14 mol) were added. A solution ofmethyl chloroformate (529.30 g, 5.60 mol) in chloroform (1250 ml) wasadded dropwise at 10° C. or below. After completion of the addition, themixture was stirred at the same temperature for 30 min. The reactionmixture was washed successively with water (1250 ml), 2N hydrochloricacid (1250 ml), water (630 ml) and saturated aqueous sodium hydrogencarbonate (630 ml), and dried over sodium sulfate. After filtration, theresidue was concentrated under reduced pressure to give a crude objectsubstance (834.02 g) as a brown oil.Step 4

Preparation of 3-chloro-2-fluorobenzylzinc bromide tetrahydrofuransolution

Under an argon stream, zinc powder (113.02 g, 1.73 mol) was suspended intetrahydrofuran (350 ml), and 1,2-dibromoethane (1.207 ml, 14.00 mmol)and trimethylsilyl chloride (8.88 ml, 70.00 mmol) were added at 60° C.The mixture was stirred with heating at 30 min. A solution of3-chloro-2-fluorobenzyl bromide (406.73 g, 1.82 mol) in tetrahydrofuran(700 ml) was added dropwise at 60° C. The mixture was stirred withheating for 1 hr to give a solution of 3-chloro-2-fluorobenzylzincbromide.

(Main Step)

The crude product (834.02 g) obtained in Step 3 was dissolved intetrahydrofuran (1060 ml), anddichlorobis(triphenylphosphine)palladium(II) (19.65 g, 28.00 mmol) wasadded under an argon stream and a solution of3-chloro-2-fluorobenzylzinc bromide (1.82 mol) was added dropwise at 60°C. After completion of the addition, the mixture was heated under refluxfor 1.5 hrs. After allowing the mixture to cool, toluene (2120 ml) and20% aqueous ammonium chloride solution (1410 ml) were added to thereaction solution, and the mixture was stirred and partitioned. Theorganic layer was washed twice with 20% aqueous ammonium chloridesolution (710 ml) and twice with saturated aqueous sodium hydrogencarbonate (710 ml) and dried over magnesium sulfate. After filtration,the filtrate was concentrated under reduced pressure to give a crudeproduct (849.34 g) as a brown oil.Step 5

The crude product (849.34 g) obtained in Step 4 was dissolved inisopropanol (1100 ml) and 4N aqueous sodium hydroxide solution (1050 ml,4.20 mmol) was added. The mixture was stirred with heating at 50° C. for1.5 hrs. Activated carbon (37 g) was added to the reaction solution andthe mixture was stirred at room temperature for 30 min. The mixture wasfiltered through Celite and 6N hydrochloric acid (740 ml) and ethylacetate (3650 ml) were added to the filtrate. The mixture was stirredand partitioned. The organic layer was concentrated under reducedpressure and the residue was suspended in isopropanol (1070 ml). Themixture was stirred at 60° C. for 1 hr. After allowing the mixture tocool, the solid was collected by filtration. The obtained solid waswashed with isopropanol (740 ml) and vacuum-dried to give an objectproduct (446.51 g, yield 73%) as a pale-yellow solid.

¹H NMR(DMSO-d₆ 400 MHz) (δ) ppm: 0.71 (3H, d, J=6.5 Hz), 1.13 (3H, d,J=6.5 Hz), 2.36 (1H, br), 3.77(1H, br), 3.94 (1H, br), 4.25 (2H, s),4.77(1H, br), 5.16 (1H, t, J=2.4 Hz), 7.19-7.23(1H, m), 7.32-7.35 (1H,m), 7.48-7.52 (1H, m), 8.24-8.28 (2H, m), 9.00 (1H, s), 15.00 (1H, s)

MS(ESI): M+ 436Step 6

The compound (443.59 g, 1.02 mol) obtained in Step 5 was dissolved inmethanol (2400 ml), and a 28% sodium methoxide in methanol (2077 ml,10.17 mol) and water (44.30 ml, 2.46 mol) were added. The mixture washeated under reflux for 17.5 hrs. Activated carbon (22 g) was added tothe reaction solution and the mixture was stirred at room temperaturefor 1 hr. The mixture was filtered through Celite and the filtrate wasconcentrated under reduced pressure. Water (1770 ml) was added to theresidue and the mixture was stirred with ice-cooling for 1 hr. Then, 6Nhydrochloric acid (1790 ml) was further added and the mixture wasstirred at room temperature for 2 hrs. Ethyl acetate (1770 ml) was addedand to the mixture was stirred and partitioned. The organic layer waswashed twice with 10% brine (890 ml), and dried over sodium sulfate.After filtration, the filtrate was concentrated under reduced pressure,and a part of the residue was recrystallized several times (finalrecrystallization solvent was methanol-water) to give an object product(28.60 g, yield 67%) as a white solid.

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.72 (3H, d, J=6.5 Hz), 1.16 (3H, d,J=6.5 Hz), 2.30-2.50 (1H, m), 3.70-3.90 (1H, m), 3.90-4.00 (1H, m), 4.03(3H, s), 4.12 (2H, s), 4.80-4.90 (1H, m), 5.19 (1H, t, J=5.2 Hz),7.19-7.25 (2H, m), 7.46-7.51 (2H, m), 8.04 (1H, s), 8.88 (1H, s), 15.44(1H, s)

MS (ESI): M+ 448

EXAMPLE 4-33

Step 1

2,4-Difluorobenzoic acid (600.00 g, 3.80 mol) was dissolved in conc.sulfuric acid (2400 ml) and N-iodosuccinimide (854.40 g, 3.60 mol) wasadded by portions at 5° C. or below. After completion of the addition,the mixture was stirred at the same temperature for 3 hrs. The reactionmixture was poured into ice water (ca. 10 L) and 10% aqueous sodiumsulfite solution (40 ml) was added. The mixture was stirred for 30 min.The precipitate was collected by filtration. To be suspended in water(ca. 3 L) and filtration were repeated until the filtrate became notless than pH 3. The obtained wet solid (1677 g) were recrystallized from50% aqueous ethanol (3000 ml) to give an object product (824.70 g, yield76%) as a white solid.

¹H NMR(CDCl₃ 300 MHz) (δ) ppm: 6.94 (1H, dd, J=10.3, 10.3 Hz), 8.46 (1H,d, J=7.5 Hz)Step 2

The compound (150.00 g, 0.53 mol) obtained in Step 1 was dissolved inethyl acetate (750 ml), and oxalyl chloride (51.0 ml, 0.581 mol) anddimethylformamide (catalytic amount) were added. The mixture was stirredat room temperature for 3.5 hrs. After filtering the reaction solution,the filtrate was concentrated under reduced pressure. After the residuewas dissolved in toluene (150 ml), the mixture was concentrated underreduced pressure, and repeated again. Tetrahydrofuran (300 ml) was addedto dissolve the residue, and the obtained solution was added dropwise toa solution of ethyl 3,3-dimethylaminoacrylate (83.2 g, 0.581 mol) andtriethylamine (96 ml, 0.686 mol) in tetrahydrofuran (450 ml). Themixture was heated under reflux for 15 hrs. After allowing the mixtureto cool, the reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure. Ethyl acetate (750 ml) was added-todissolve the residue. The mixture was washed successively with aqueousammonium chloride (400 ml), saturated aqueous sodium hydrogen carbonate(200 ml) and saturated brine, and dried over sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure to givea crude object substance (206.50 g) as a brown oil.Step 3

The crude product (206.50 g) obtained in Step 2 was dissolved intetrahydrofuran (800 ml), and (S)-(+)-tert-leucinol hydrochloride (81.10g, 0.53 mol) and triethylamine (74 ml, 0. 53 mol) were added. Themixture was stirred at room temperature for 50 min. After filtration ofthe reaction mixture, the filtrate was concentrated under reducedpressure and the obtained residue was dissolved in dimethylformamide(1000 ml). Potassium carbonate (146.0 g, 1.06 mol) was added and themixture was stirred with heating at 90° C. for 3 hrs. With ice-cooling,water (700 ml) was added to the reaction mixture and the precipitate wascollected by filtration and washed with water. The solid collected byfiltration was suspended in 30% aqueous ethanol (1000 ml) and collectedby filtration. This operation was repeated with a mixture ofhexane:diethyl ether=1:1. After filtration, the filtrate wasvacuum-dried to give an object product (184.74 g, yield 76%) as a whitesolid.

¹H NMR(DMSO-d₆ 400 MHz) (δ) ppm: 0.968(9H, s), 1.27 (3H, t), 3.96-3.98(2H, m), 4.18-4.27 (2H, m), 4.80 (1H, t, J=7.0 Hz), 5.05 (1H, br),8.22(1H, d, J=11.2 Hz), 8.60 (1H,.s), 8.61 (1H. d, J=7.2 Hz)Step 4

The compound (150.00 g, 0.33 mol) obtained in Step 3 was dissolved indimethylformamide (600 ml), and imidazole (28.80 g; 0.42 mol) andtert-butyldimethylsilyl chloride (28.80 g, 0.42 mol) were added. Themixture was stirred at room temperature for 6 hrs. Water (1200 ml) wasadded to the reaction mixture and the mixture was extracted with ethylacetate (800 ml). The organic layer was washed 3 times with water, andthen with saturated brine and dried over sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure and theobtained residue was purified by silica gel chromatography (ethylacetate:hexane=1:3 to 1:2) to give an object product (164.30 g, yield88%) as a white amorphous form.

¹H NMR(CDCl₃ 300 MHz) (δ) ppm: −0.08 (3H, s), 0.00 (3H, s), 0.67(9H, s),1.06(9H,s), 1.41(3H, t, J=7.1 Hz), 4.05-4.18(2H, m), 4.36-4.43 (3H, m),7.32(1H, d, J=10.3 Hz), 8.65 (1H, s), 8.95(1H, d, J=7.4 Hz)Step 5

The compound (75.0 g, 0.13 mol) obtained in Step 4 was dissolved intetrahydrofuran (580 ml). Under an argon stream,bis(dibenzylideneacetone)palladium(0) (2.99 g, 5.20 mmol) andtri(2-furyl)phosphine (2.41 g, 10.38 mmol) were added, and a solution of3-chloro-2-fluorobenzylzinc bromide (0.1.7 mol) in tetrahydrofuran wasadded dropwise at 60° C. After completion of the addition, the mixturewas heated under reflux for 2 hrs. After allowing the mixture to cool,ethyl acetate (75 ml) and saturated aqueous ammonium chloride solution(38 ml) were added to the reaction solution. The mixture was stirred atroom temperature for 30 min. and partitioned. The organic layer waswashed twice with water (75 ml) and then with saturated brine (200 ml),and dried over sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure and the obtained residue waspurified by silica gel chromatography (ethyl acetate:hexane=1:2 to 11:1)to give an object product (66.80 g, yield 73%) as a brown amorphousform.

¹H NMR(CDCl₃ 300 MHz) (δ) ppm: −0.10 (3H, s), −0.01(3H, s), 0.64 (9H,s), 1.06 (9H, s), 1.40 (3H, t, J=7.1 Hz), 4.04-4.15 (4H, m),4.35-4.46(3H, m), 6.95-7.03(2H, m), 7.24-7.31 (2H, m), 8.38 (1H, d,J=8.8 Hz), 8.66(1H, s)Step 6

The compound (2.41 g, 4.07 mmol) obtained in Step 5 was dissolved inmethanol (20 ml), and 28% sodium methoxide in methanol (8.4 ml, 40.70mmol). and water (0.15 ml, 8.14 mmol) were added. The mixture was heatedunder reflux for 18 hrs. Water (1.4 ml) was added to the reactionsolution and the mixture was stirred at room temperature for 1.5 hrs andfiltered with Celite. The filtrate was concentrated under reducedpressure, and water (2.5 ml) and 2N hydrochloric acid (20 ml) were addedto the residue. The mixture was stirred for 5 min and extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over sodium sulfate. After the filtration, the filtratewas concentrated under reduced pressure. The residue was sonicated withhexane (20 ml) and, after standing still, hexane was removed bydecantation. This was repeated three times. Diethyl ether (30 ml) wasadded to the residue and the mixture was sonicated. The solid wascollected by filtration and the obtained solid was dissolved by heatingin ethyl acetate (15 ml). Hexane (15 ml) was added and recrystallizationgave an object product (1.21 g, yield 64%) as a white solid.

¹H NMR(DMSO-d₆ 300 MHz) (δ) ppm: 0.99 (9H, s), 3.99-4.11 (7H, m),5.11-5.20 (2H, m), 7.19-7.25 (2H, m), 7.49-7.52 (2H, m), 8.03 (1H, s),8.78(1H, s), 15.39(1H, s)

MS(ESI): M+ 462

EXAMPLE 4-37

Step 1

3-Methoxy-2-nitrobenzoic acid (20.00 g, 0.10 mol) was dissolved indimethylformamide (100 ml), and potassium carbonate (28.10 g, 0.20 mol)and methyl iodide (7.60 ml, 0.12 mol) were added. The mixture wasstirred at room temperature for 1 hr. The reaction mixture was added towater (300 ml) and the mixture was stirred. The precipitate wascollected by filtration, washed with water (200 ml) and vacuum-dried togive a crude object substance (23.90 g) as a white solid.Step 2

The crude product (23.90 g) obtained in Step 1 was suspended in amixture of tetrahydrofuran (150 ml) and methanol (50 ml), and 5%palladium-carbon (wet)(2.30 g) was added. The mixture was -stirred undera hydrogen atmosphere at room temperature for 19.5 hrs. Ethyl acetate(200 ml) was added to the reaction mixture and the mixture was filteredwith Celite. The filtrate was concentrated under reduced pressure andthe water was removed azeotropically with toluene to give a crudeproduct (18.80 g) as a brown oil.Step 3

The crude product (18.80 g) obtained in Step 2 was dissolved indimethylformamide (200 ml), and N-bromosuccinimide (17.98 g, 0.10 mol)was added by portions at 5° C. After completion of the addition, themixture was stirred at the same temperature for 30 min. The reactionmixture was poured into water (500 ml) and extracted twice with ethylacetate (300 ml). The organic layer was washed successively with water(300 ml), saturated aqueous sodium hydrogen carbonate and saturatedbrine, and dried over sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure and the obtained residue waspurified by silica gel chromatography (chloroform) to give an objectproduct (25.11 g, yield 95%) as a yellow oil.

¹H NMR(CDCl₃ 300 MHz) (δ) ppm: 3.86 (6H, s), 6.02 (.2H, brs), 6.90 (1H,s), 7.60 (1H, s)Step 4

The compound (25.11 g, 96.54 mmol) obtained in Step 3 was suspended inwater (50 ml) and conc. hydrochloric acid (25 ml) was added. An aqueoussolution (100 ml) of sodium nitrite (7.33 g, 106.22 mmol) was addeddropwise at 5° C. After completion of the addition, the mixture wasstirred at the s same temperature for 5 min. This reaction solution wasadded dropwise to a solution of copper (I) chloride (9.55 g, 96.47 mmol)in conc. hydrochloric acid (75 ml) at room temperature. After completionof the addition, the mixture was stirred at room temperature for 13 hrs.Water (200 ml) was added to the reaction solution and the mixture wasextracted with ethyl acetate (400 ml). The organic layer was washedsuccessively with water (400 ml) and saturated brine, and dried oversodium sulfate. After filtration, the filtrate was, concentrated underreduced pressure to give an object product (15.18 g, yield 56%) as anorange solid.

¹H NMR(CDCl₃ 300 MHz) (δ) ppm: 3.92 (3H, s), 3.93 (3H, s), 7.16 (1H, d,J=2.1 Hz), 7.49 (1H, d, J=2.2 Hz)Step 5

The compound (74.80 g, 0.27 mol) obtained in Step 4 was dissolved indichloromethane (300 ml) and 1M boran tribromide/dichloromethanesolution (700 ml, 0.70 mol) was added dropwise at 10° C. or below. Aftercompletion of the addition, the mixture was stirred at room temperaturefor 1.5 hrs. The reaction mixture was added to ice water (1500 ml) andthe precipitated solid was collected by filtration. The filtrate waspartitioned, and the aqueous layer was extracted with ethyl acetate (200ml). The organic layers were combined and concentrated under reducedpressure. The solid collected by filtration and the residue weredissolved in diethyl ether (1000 ml) and 1N aqueous sodium hydroxidesolution (1000 ml) was added for extraction. 2N Hydrochloric acid (500ml) was added to the aqueous layer. The mixture was stirred andextracted with ethyl acetate (800 ml). The mixture was partitioned andthe organic layer was washed successively with water and saturatedbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure to give an object product (63.83 g, yield 95%) as abeige solid.

¹H NMR(DMSO-d₆ 300 MHz) (δ) ppm: 7.23(1H, d, J=2.4 Hz), 7.28 (1H, d,J=2.4 Hz), 10.99(1H, s), 13.55 (1H, brs)Step 6

The compound (63.83 g, 0.25 mol) obtained in Step 5 was dissolved indimethylformamide (400 ml), and potassium carbonate (87.70 g, 0.64 mol)and ethyl iodide (81.20 ml, 1.02 mol) were added. The mixture wasstirred with heating at 50° C. for 3 hrs, and saturated aqueous ammoniumchloride (600 ml) and ethyl acetate (400 ml) were added to thereaction-mixture. The mixture was partitioned and the aqueous layer wasextracted with ethyl acetate (400 ml). The organic layers were. combinedand washed successively with brine (3 times) and saturated brine, driedover sodium sulfate, filtered, and concentrated under reduced pressureto give an object product (76.38 g, yield 98%) as a brown solid.

¹H NMR(CDCl₃ 400 MHz) (δ) ppm: 1.39 (3H, t, J=7.2 Hz), 1.48 (3H, t),4.11(2H, q), 4.38 (2H, q, J=7.2 Hz), 7.12 (1H, d, J=2.0 Hz), 7.42 (1H,d, J=2.0 Hz)Step 7

The compound (76.38 g, 0.25 mol) obtained in Step 6 was dissolved inethanol (250 ml), and 8N aqueous sodium hydroxide-solution (62.00 ml,0.50 mol) was added. The mixture was stirred with heating at 50° C. for30 min. 2N Hydrochloric acid (250 ml) was added to the reaction solutionwith ice-cooling and the mixture was stirred, and extracted twice withethyl acetate (350 ml). The organic layer was washed successively withwater and saturated brine, and dried over sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure to givean object product (68.79 g yield 99%) as a pale-brown solid.

¹H NMR(CDCl₃ 400 MHz) (δ) ppm: 1.50 (3H, t, J=-6.8 Hz), 4.12 (2H, q,J=6.8 Hz), 7.19 (1H, d, J=2.4 Hz), 7.65(1H, d, J=2.4 Hz)Step 8

The compound (85.17 g, 0.31 mol) obtained in Step 7 was dissolved intoluene (450 ml), and thionyl chloride(44.40 ml, 0.61 mol) anddimethylformamide (catalytic amount) were added. The mixture was stirredat 90° C. for 1 hr. After allowing the mixture to cool, the reactionsolution was concentrated under reduced pressure. After the residue wasdissolved in toluene, the mixture was concentrated under reducedpressure. This was repeated two more times. The residue was dissolved intetrahydrofuran (250 ml) and the obtained solution was added dropwise toa solution of ethyl 3,3-dimethylaminoacrylate (43.60 g, 0.31 mol) andtriethylamine (50.90 ml, 0.37 mol) in tetrahydrofuran (200 ml). Themixture was heated under reflux for 15 hrs. After allowing the mixtureto cool, water (300 ml) and ethyl acetate (500 ml) were added to thereaction mixture. The mixture was stirred and partitioned. The organiclayer was washed successively with water (300 ml) and saturated brine,and dried over sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure to give a crude object substance(124.80 g) as a brown oil.Step 9

The crude product (124.80 g) obtained in Step 8 was dissolved intetrahydrofuran (500 ml), and (S)-(+)-tert-leucinol hydrochloride (46.80g, 0.31 mol) and triethylamine (42.50 ml, 0.31 mol) were added. Themixture was stirred at room temperature for 40 min. After filtration ofthe reaction mixture, the filtrate was concentrated under reducedpressure. The obtained residue was dissolved in ethyl acetate (800 ml),washed twice with water, and then with saturated brine, and dried oversodium sulfate. After the filtration, the filtrate was concentratedunder reduced pressure to give a crude object substance (131.30 g) as abrown oil.Step 10

The crude product (131.30 g) obtained in Step 9 was dissolved indimethylformamide (400 ml), and imidazole (27.00 g, 0.40 mol) andtert-butyldimethylsilyl chloride (41.30 g, 0.27 mol) were added. Themixture was stirred at room temperature for 14 hrs. Water was added tothe reaction solution and the mixture was extracted twice with ethylacetate (500 ml). The organic layer was washed three times with waterand then with saturated brine, and dried over sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure to givea crude-object substance.(159.80 g) as a brown oil.Step 11

The crude product (159.80 g) obtained in Step 10 was dissolved intoluene (1100 ml), and sodium hydride (15.80 g, 0.40 mol) was added. Themixture was stirred with heating at 100° C. for 14 hrs. In Hydrochloricacid (400 ml) was added to the reaction solution under ice-cooling andthe mixture was stirred and partitioned. The organic layer was washedsuccessively with water and saturated brine, and dried over sodiumsulfate. After filtration, the filtrate was concentrated under reducedpressure and the obtained residue was dissolved in dimethylformamide(500 ml). Potassium carbonate (42.10 g, 0.31 mol) and ethyl iodide(24.40 ml, 0.31 mol) was added and the mixture was stirred with heatingat 50° C. for 1.5 hrs. A saturated aqueous ammonium chloride solution(400 ml) was added to the reaction solution under ice-cooling, and themixture was stirred and extracted twice with ethyl acetate. The organiclayer was washed successively with water, twice with brine and saturatedbrine, and dried over sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure and the obtained residue waspurified by silica gel chromatography (ethyl acetate:hexane=1:3 to 2:3)to give an object product (76.50 g, yield 45%) as a brown oil.

¹H NMR(CDCl₃ 400 MHz) (δ) ppm: −0.05 (3H, s), 0.01 (3H, s), 0.73 (9H,s), 0.98 (9H, s), 1.40(3H, t), 1.53-1.59 (3H, m), 4.10-4.24 (4H, m),4.34-4.44(2H,m), 6.10-6.14(1H, m), 7.22 (1H, s), 8.32 (1H, t, J=2.4 Hz),8.70 (1H, s)Step 12

The compound (76.50 g, 0.14 mol) obtained in Step 11 was dissolved intetrahydrofuran (500 ml), and under an argon stream,bis(dibenzylideneacetone)palladium(0) (3.17 g, 5.51 mmol) andtri(2-furyl)phosphine (2.56 g, 11.03 mmol) were added. A solution of3-chloro-2-fluorobenzylzinc bromide (0.28 mol) in tetrahydrofuran wasadded dropwise at 60° C. After completion of the addition, the mixturewas cheated under reflux for 2.5 hrs. After allowing the mixture tocool, saturated aqueous ammonium chloride solution (600 ml) was added tothe reaction solution. The mixture was stirred at room temperature for 1hr and filtered with Celite. After the mixture was partitioned, theaqueous layer was extracted with ethyl acetate twice. The organic layer,on the other hand, was concentrated under reduced pressure, and theresidue was dissolved in ethyl acetate. All ethyl acetate layers werecombined and washed successively with 1N hydrochloric acid and saturatedbrine, and dried over sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The obtained residue was dissolvedin dimethylformamide (400 ml) and potassium carbonate (19.00 g, 0.14mol) and ethyl iodide (11.00 ml, 0.14 mol) were added. The mixture wasstirred with heating at 50° C. for 1.5 hrs. A saturated aqueous ammoniumchloride solution (400 ml) was added to the reaction mixture withice-cooling, and the mixture was stirred and extracted with ethylacetate (500 ml). The organic layer was washed with water, brine (twice)and saturated brine, and dried over sodium sulfate. After filtration,the filtrate was concentrated under reduced pressure and the obtainedresidue was purified by silica gel chromatography (ethylacetate:hexane=1:2 to 1:1) to give an object product (72.10 g, yield85%) as a brown oil.

¹H NMR(CDCl₃ 400 MHz) (δ) ppm: −0.07 (3H, s), 0.00 (3H, s), 0.70 (9H,s), 1.24 (9H, s), 1.39 (3H, t, J=7.2 Hz), 1.51-1.54 (3H, m), 4.05 (2H,s), 4.07-4.19 (4H, m), 4.33-4.45(2H, m), 6.12-6.15 (1H, m), 6.99-7.02(2H, m), 7.04-7.09 (1H, m), 7.19-7.25 (1H, m), 8.06 (1H, d, J=2.4 Hz),8.69 (1H, s)Step 13

The compound (65.80 g, 0.11 mol) obtained in Step 12 was dissolved inethanol (200 ml) and 1N aqueous sodium hydroxide solution (640 ml, 0.64mol) was added. The mixture was heated under reflux for 2 hrs. 2NHydrochloric acid (350 ml) was added to the reaction solution withice-cooling and the mixture was stirred and extracted twice with ethylacetate. The organic layer was washed successively with water andsaturated brine, and dried over sodium sulfate. After filtration, thefiltrate was concentrated under reduced pressure, and diethyl ether (500ml) was added the residue. The mixture was sonicated and the obtainedsolid was collected by filtration. The collected solid was added toethyl acetate (250 ml) and dissolved with heating. Hexane (50 ml) wasadded and the precipitated solid was collected by filtration,vacuum-dried to give an object product (41.10 g, yield 81%) as a whitesolid.

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.93 (9H, s), 1.49 (3H, t, J=6.9 Hz),4.00 (2H, t, J=6.4 Hz), 4.20 (2H, s), 4.22-4.33 (2H, m), 5.12 (1H, t),6.36 (1H, t, J=6.8 Hz), 7.21 (1H, m), 7.39-7.48 (,2H, m), 7.54 (1H, s),7.79 (1H, s), 8.79 (1H, s), 15.04 (1H, s)

MS (ESI): M+ 476

EXAMPLES 1-3-1-102, 2-1-2-8, 3-1-3-86, 4-1-4-54

In the same manner as in Examples 1-1 and 1-2 and the above-mentionedExamples, the compounds of Examples 1-3-1-102, 2-1-2-8, 3-1-3-86 and4-1-4-54 were obtained. The chemical structures thereof are shown inTables 1, 2, 3 and 4.

EXPERIMENTAL EXAMPLES

The following explains evaluation methods of the HIV integraseinhibitory activity of the compound of the present invention.

(i) Construction of Recombinant Integrase Gene Expression System

The 185th phenylalanine of HIV integrase full length gene (J. Virol.,67, 425-437 (1993)) was substituted by histidine and inserted into therestriction enzyme NdeI and XhoI sites of plasmid pET21a(+) (Novagen),whereby an integrase expression vector pET21a-IN-F185H was constructed.

(ii) Production and Purification of Integrase Protein

Escherichia coli recombinant BL21(DE3) transformed with plasmidpET21a-IN-F185H obtained in (i) was shake cultured at 30° C. in a liquidmedium containing ampicillin. When the culture reached the logarithmicgrowth phase, isopropyl-β-D-thiogalactopyranoside was added to promoteexpression of integrase gene. The culture was continued for 3 hrs topromote accumulation of the integrase protein. The recombinant E. coliwas collected in pellets by centrifugal separation and preserved at −80°C.

The E. coli was suspended in Lysis buffer (20 mM HEPES (pH 7.5), 5 mMDTT, 10 mM CHAPS, 10% glycerol) containing 1M sodium chloride andsubjected to repeat pressurization and depressurization for rupture, andcentrifugal separation at 4° C., 40,000×g, 60 min to recover awater-soluble fraction (supernatant). This was diluted 10-fold withLysis buffer free of sodium chloride, mixed with SP-Sepharose (PharmaciaCorporation) and stirred at 4° C. for 60 min to allow adsorption ofintegrase protein to the resin. The resin was washed with Lysis buffercontaining 100 mM sodium chloride and the integrase protein was elutedwith Lysis buffer containing 1M sodium chloride.

The eluted integrase protein solution was applied to a Superdex 75(Pharmacia Corporation) column for gel filtration. The protein waseluted with Lysis buffer containing 1M sodium chloride.

The obtained fractions of the integrate protein were collected andpreserved at −80° C.

(iii) Preparation of DNA Solution

The following DNA synthesized by Greiner was dissolved in TE buffer (10mM Tris-hydrochloric acid (pH 8.0), 1 mM EDTA) and mixed with donor DNA,target DNA, each complementary strand (+ and − strands) to 1 μM. Themixture was heated at 95° C. for 5 min, 80° C. for 10 min, 70° C. for 10min, 60° C. for 10 min, 50° C. for 10 min and 40° C. for 10 min andpreserved at 25° C. to give a double stranded DNA, which was used forthe test. Donor DNA (− strand having biotin attached to the 5′ terminal)Donor + strand: 5′-Biotin-ACC CTT TTA GTC AGT GTG (SEQ ID NO: 1) GAA AATCTC TAG CA-3′ Donor − strand: 5′-ACT GCT AGA GAT TTT CCA CAC TGA (SEQ IDNO: 2) CTA AAA G-3′ Target DNA (+, − strands both having digoxigeninadded at 3′ terminal) Target + strand: 5′-TGA CCA AGG GCT AAT TCACT-Dig-3′ (SEQ ID NO: 3) Target − strand: 5′-AGT GAA TTA GCC CTT GGTCA-Dig-3′ (SEQ ID NO: 4)(iv) Determination of Enzyme (HIV Integrase) Inhibitory activity

The donor DNA was diluted with TE buffer to 10 nM, of which 50 μl wasadded to each well of streptavidin-coated microtiter plate (Roche) andallowed to adsorb at 37° C. for 60 min. The DNA was washed withphosphate buffer (Dulbecco PBS, Sanko Junyaku Co., Ltd.) containing 0.1%Tween 20 and phosphate buffer. Then, a reaction mixture (70 μl) havingthe following composition, a test substance (10 μl) diluted with thereaction mixture and 100 μl/ml integrase protein (10 μl) were added toeach well and reacted at 37° C. for 60 min.

Then, 50 nM target DNA (1.0 μl) was added, reacted at 37° C. for 10 minand washed with phosphate buffer containing 0.1% Tween 20 to stop thereaction.

Then, 100 mU/ml peroxidase labeled anti-digoxigenin antibody solution(Roche, 100 μl) was added, and the mixture was reacted at 37° C. for 60min, followed by washing with phosphate buffer containing 0.1% Tween 20.

A peroxidase color solution (Bio Rad, 100 μl) was added and allowed toreact at room temperature for 4 min. The color reaction was stopped byadding 1N sulfuric acid (100 μl). The absorbance at 450 nm was measured.

The HIV integrase inhibitory activity (IC₅₀) of the compound of thepresent invention was calculated from the inhibition rate according tothe following formula. The results are shown in Tables 5, 6 and 7.inhibition rate (%)=[1-(Object-Blank)/(Control-Blank)]×100Object; absorbance of well in the presence of test compound Control;absorbance of well in the absence of test compound Blank; absorbance ofwell in the absence of test compound, in the absence of integraseprotein.Evaluation of Antiviral Activity

The effect of combined use of the compound of the present invention withknown anti-HIV agents can be determined as shown below.

For example, the effect of two-drug use of an existing nucleosidereverse transcriptase inhibitor (Zidovudine, Lamivudine, Tenofovir), anon-nucleoside reverse transcriptase inhibitor (Efavirenz) or a proteaseinhibitor (Indinavir, Nelfinavir) and a test substance A, and the likeare evaluated in an acute infection system using HIV-1 IIIB-infectedCEM-SS cells by the XTT method.

In addition, the effect of three-drug use of test substance A,Zidovudine and Lamivudine, or test substance A, Tenofovir and Lamivudineand the like is evaluated.

Prior to the combined use test, IC₅₀ and CC₅₀ of each pharmaceuticalagent alone are determined. The effect of two-drug use is evaluatedbased on the combination of five concentrations of pharmaceutical agentA and nine concentrations of pharmaceutical agent B, which have beendetermined based on the above results. For three-drug use, highconcentrations of pharmaceutical agent B and pharmaceutical agent C aremixed and the obtained concentrations are combined with theconcentrations of pharmaceutical agent A for evaluation.

The experimental data of the test substance and pharmaceutical agent tobe combined in the case of single use and combined use are analyzed.bythe programs of Prichard and Shipman MacSynergy II version 2.01 andDelta graph version 1.5d. A three dimensional plot is created at a 95%(or 68%, 99%) confidence level, from the percent inhibition at theconcentration of each combined pharmaceutical agent, which is obtainedfrom triplicate experiments, and the effect of combined use is evaluatedbased on the numerical values of μM²% calculated therefrom. Theevaluation criteria are shown in the following. definition ofinteraction μM² % highly synergistic  >100 slightly synergistic +51 to+100 additive +50 to −50  slightly antagonistic −51 to −100 highlyantagonistic <−100

TABLE 1 1-1

1-2

1-3

1-4

1-5

1-6

1-7

1-8

1-9

1-10

1-11

1-12

1-13

1-14

1-15

1-16

1-17

1-18

1-19

1-20

1-21

1-22

1-23

1-24

1-25

1-26

1-27

1-28

1-29

1-30

1-31

1-32

1-33

1-34

1-35

1-36

1-37

1-38

1-39

1-40

1-41

1-42

1-43

1-44

1-45

1-46

1-47

1-48

1-49

1-50

1-51

1-52

1-53

1-54

1-55

1-56

1-57

1-58

1-59

1-60

1-61

1-62

1-63

1-64

1-65

1-66

1-67

1-68

1-69

1-70

1-71

1-72

1-73

1-74

1-75

1-76

1-77

1-78

1-79

1-80

1-81

1-82

1-83

1-84

1-85

1-86

1-87

1-88

1-89

1-90

1-91

1-92

1-93

1-94

1-95

1-96

1-97

1-98

1-99

1-100

1-101

1-102

TABLE 2 2-1

2-2

2-3

2-4

2-5

2-6

2-7

2-8

TABLE 3 3-1

3-2

3-3

3-4

3-5

3-6

3-7

3-8

3-9

3-10

3-11

3-12

3-13

3-14

3-15

3-16

3-17

3-18

3-19

3-20

3-21

3-22

3-23

3-24

3-25

3-26

3-27

3-28

3-29

3-30

3-31

3-32

3-33

3-34

3-35

3-36

3-37

3-38

3-39

3-40

3-41

3-42

3-43

3-44

3-45

3-46

3-47

3-48

3-49

3-50

3-51

3-52

3-53

3-54

3-55

3-56

3-57

3-58

3-59

3-60

3-61

3-62

3-63

3-64

3-65

3-66

3-67

3-68

3-69

3-70

3-71

3-72

3-73

3-74

3-75

3-76

3-77

3-78

3-79

3-80

3-81

3-82

3-83

3-84

3-85

3-86

TABLE 4 4-1

4-2

4-3

4-4

4-5

4-6

4-7

4-8

4-9

4-10

4-11

4-12

4-13

4-14

4-15

4-16

4-17

4-18

4-19

4-20

4-21

4-22

4-23

4-24

4-25

4-26

4-27

4-28

4-29

4-30

4-31

4-32

4-33

4-34

4-35

4-36

4-37

4-38

4-39

4-40

4-41

4-42

4-43

4-44

4-45

4-46

4-47

4-48

4-49

4-50

4-51

4-52

4-53

4-54

TABLE 5 Enzyme activity IC₅₀ Enzyme activity IC₅₀ Ex. No. (μM) Ex. No.(μM) 1-1 0.029 1-2 0.033 1-3 0.36 1-4 0.24 1-6 0.14 1-7 0.067 1-8 0.0461-9 0.017 1-10 0.072 1-11 0.18 1-12 0.71 1-13 0.14 1-14 0.075 1-15 0.231-16 0.032 1-17 0.084 1-18 0.12 1-19 0.081 1-20 0.69 1-21 0.074 1-220.11 1-23 0.19 1-24 0.29 1-25 0.16 1-26 0.18 1-27 0.076 1-28 0.059 1-290.24 1-30 0.14 1-31 0.17 1-32 0.068 1-33 0.14 1-34 0.35 1-36 0.18 1-370.11 1-38 0.17 1-39 0.18 1-40 0.11 1-41 0.21 1-42 0.13 1-43 0.024 1-440.051 1-45 0.21 1-46 0.42 1-47 0.098 1-48 0.38 1-49 0.053 1-50 0.11 1-510.18 1-63 0.02 1-64 0.056 1-65 0.12 1-66 0.049 1-67 0.79 1-68 0.049 1-690.074 1-70 0.082 1-71 0.013 1-72 0.025 1-73 0.031 1-74 0.098 1-75 0.0161-76 0.028 1-77 0.063 1-78 0.59 1-79 0.077 1-80 0.35 1-86 0.15 1-87 0.141-88 0.45 1-92 0.28 1-93 0.37 1-96 0.23 1-97 0.13 2-1 0.17 2-2 0.18 2-30.11 2-4 0.018 2-5 0.30 2-6 0.092 2-7 0.079 2-8 0.085

TABLE 6 Enzyme activity IC₅₀ Enzyme activity IC₅₀ Ex. No. (μM) Ex. No.(μM) 3-1 0.47 3-2 0.2 3-3 0.19 3-4 0.011 3-5 0.024 3-6 0.011 3-8 0.343-9 0.084 3-10 0.018 3-12 0.016 3-13 0.029 3-14 0.014 3-17 0.013 3-200.01 3-21 0.03 3-22 0.79 3-23 0.0072 3-24 0.039 3-25 0.069 3-26 0.0113-27 0.075 3-33 0.0087 3-34 0.011 3-35 0.011 3-36 0.051 3-37 0.011 3-380.015 3-39 0.049 3-42 0.72 3-43 0.018 3-44 0.0096 3-45 0.015 3-47 0.00863-48 0.021 3-49 0.0079 3-50 0.018 3-52 0.012 3-53 0.0079 3-54 0.00643-55 0.0087 3-56 0.012 3-57 0.015 3-58 0.008 3-59 0.008 3-60 0.0055 3-610.0076 3-62 0.027 3-63 0.017 3-64 0.018 3-65 0.015 3-66 0.048 3-670.0064 3-69 0.0043 3-72 0.0038 3-73 0.0033 3-74 0.0049 3-76 0.0085 3-770.0089 3-78 0.016 3-79 0.0067 3-80 0.0088 3-86 0.14

TABLE 7 Enzyme activity IC₅₀ Enzyme activity IC₅₀ Ex. No. (μM) Ex. No.(μM) 4-1 0.86 4-4 0.55 4-5 0.13 4-6 0.46 4-7 0.13 4-8 0.033 4-9 0.0214-11 0.22 4-12 0.065 4-13 0.30 4-15 0.031 4-16 0.0071 4-17 0.0031 4-180.0020 4-19 0.0029 4-20 0.0017 4-21 0.0045 4-22 0.0029 4-23 0.0038 4-240.0025 4-25 0.0019 4-26 0.0015 4-27 0.0029 4-28 0.0027 4-29 0.0045 4-300.0029 4-31 0.0021 4-32 0.0029 4-33 0.0020 4-34 0.0039 4-35 0.0043 4-360.0037 4-37 0.0019 4-38 0.0033 4-39 0.0041 4-40 0.0043 4-41 0.0023 4-420.0023 4-43 0.0028 4-44 0.0024 4-45 0.0034 4-46 0.0050 4-47 0.0023 4-480.0030 4-49 0.0057 4-50 0.0031

NMR and MS data of the Example compounds shown in the above-mentionedTable 1 to Table 4 are described in the following.

EXAMPLE 1-1

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.75(2H, t, J=4.7 Hz), 4.36(2H, s),4.60(2H, t, J=4.8 Hz), 4.98(1H, brs), 7.37-7.39(1H, m), 7.45(1H, dd,J=1.4, 7.6 Hz), 7.57(1H, dd, J=1.5, 8.0 Hz), 7.81(1H, dd, J=2.1, 8.9Hz), 8.02(1H, d, J=8.8 Hz), 8.15(1H, d, J=1.8 Hz),8.86(1H, s), 15.18(1H,brs)

MS (ESI): M+ 392

EXAMPLE 1-2

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.78 (2H, m), 4.35 (2H, s), 4.64 (2H,m), 5.00 (1H, m), 7.39 (2H, m), 7.47 (1H, m), 7.58 (1H, m), 8.00 (1H,m), 8.81 (1H, s), 14.80 (1H, s)

MS (ESI): M+ 409

EXAMPLE 1-3

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 2.85(3H, s), 3.41(2H, m), 4.37(2H, S),4.63(2H, t, J=5.6 Hz), 7.25-7.29 (1H, m), 7.39(1H, dd, J=7.8, 7.8 Hz),7.47(1H, dd, J=1.5, 7.7 Hz;), 7.58(1H, dd, J=1.5, 7.8 Hz), 7.84(1H, dd,J=2.0, 8.9 Hz), 8.00(1H, d, J=8.9 Hz), 8.15(1H, d, J=1.8 Hz), 8.91(1H,s)

MS (ESI): M+ 469

EXAMPLE 1-4

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 4.38 (2H, s), 4.46 (2H, t, J=5.9 Hz),4.90 (2H, t, J=5.9 Hz), 6.84 (1H, s), 7.14 (1H, S), 7.37-7.47. (3H, m),7.59 (1H, m), 7.82 (1H, m), 8.01 (1H, m), 8.15 (1H, s), 8.66 (1H, s),14.99 (1H, s)

MS (ESI): M+ 441

EXAMPLE 1-5

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 2.87 (3H, s), 3.12 (3H, s), 4.35 (2H,s), 5.59 (2H, s), 7.38-7.45 (2H, m), 7.-57 (1H, m), 7.-71-7.76 (2H, m),8.12 (1H, s), 8.94 (1H, s)

MS (ESI): M+ 432

EXAMPLE 1-6

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 2.64 (3H, d, J=4.4), 4.35 (2H, s),5.24 (2H, s), 7.35-7.47 (2H, m), 7.56-7.65 (2H, m), 7.80 (1H, m), 8.13(1H, s), 8.32 (1H, q, J=4.4 Hz), 9.00 (1H, s)

MS (ESI): M+ 418

EXAMPLE 1-7

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 4.36 (2H, s), 5.23 (2H, s), 7.35-7.45(2H, m), 7.54-7.65 (3H,m), 7.83-7.88 (2H, m), 8.13 (1H, s), 9.01 (1H, s)

MS (ESI): M+ 404

EXAMPLE 1-8

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 1.57 (6H, d, J=6.5 Hz), 4.37 (2H, s),5.24 (1H, m), 7.38 (1H, dd, J=7.7, 7.7 Hz) 7.46 (1H, dd, J=1.6, 7.7 Hz),7.58 (1H, dd, J=1.6, 7.7 Hz), 7.85 (1H, dd, J=2.1, 8.9 Hz), 8.15-8.18(2H, m), 8.86 (1H, s)

MS (ESI): M+ 389

EXAMPLE 1-9

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 4.35 (2H, s), 5.98 (2H, s), 7.37-7.44(4H, m), 7.57 (1H, m), 7.83 (1H, m), 8.10-8.12 (2H, m), 8.99 (1H, s)

MS (ESI): M+ 440

EXAMPLE 1-10

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 2.85 (2H, Mm), 4.36 (2H, s), 4.74 (2H,m), 7.38-7.46 (2H, m), 7.58 (1H, m), 7.85 (1H, m), 8.00 (1H, m), 8.14(1H, s), 9.00 (1H, s)

MS (ESI): M+ 419

EXAMPLE 1-11

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.74 (2H, dt, J=4.8, 5.6 Hz), 4.59(2H, t, J=4.9 Hz), 4.66 (2H, s), 4.98 (1H, t, J=5.6 Hz), 7.48-7.53 (4H,m), 7.85-8.08 (5H, m), 8.18 (1H, m), 8.83 (1H, s), 15.24 (1H, brs)

MS (ESI): M+ 373

EXAMPLE 1-12

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.70 (2H, m), 3.72 (3H, s), 4.27 (2H,s), 4.38 (2H, m), 4.96 (1H, br), 7.32-7.41 (2H, m), 7.54 (1H, dd, J=1.8,7.3 Hz), 7.61 (1H, dd, J=2.2, 8.8 Hz), 7.76 (1H, d, J=8.8. Hz), 8.00(1H, d, J=2.2 Hz), 8.55 (1H, s)

MS (ESI): M+ 405

EXAMPLE 1-13

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 2.67 (2H, m), 4.37 (2H, s), 4.73 (2H,m), 6.97 (1H, br), 7.38-7.48 (3H, m), 7.58 (1H, m), 7.87 (1H, m), 8.01(1H, -m), 8.15 (1H, s), 8.93 (1H, s)

MS (ESI): M+ 418

EXAMPLE 1-14

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 2.30 (3H, s), 4.34 (2H, s), 5.62 (2H,s), 7.37 (1H, m), 7.44 (1H, m), 7.55 (1H, m), 7.72-7.78 (2H, m), 8.10(1H, s), 8.90 (1H, s)

MS (ESI): M+ 403

EXAMPLE 1-15

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 4.31 (2H, s), 5.84 (2H, s), 7.26-7.41(7H, m), 7.55 (1H, m), 7.73 (1H, m), 7.83 (1H, m), 8.13 (1H, m), 9.23(1H, s), 15.18 (1H, brs)

MS (ESI): M+ 437

EXAMPLE 1-16

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.12 (2H, t, J=7.3 Hz), 4.38 (2H, s),4.78 (2H, t, J=7.3 Hz), 7.20-7.28 (5H, m), 7.37-7.47 (3H, m), 7.58 (1H,m), 7.85 (1H, m), 8.09 (1H, m), 8.15 (1H, s), 8.79 (1H,s), 15.07 (1H,brs)

MS (ESI) M+ 451

EXAMPLE 1-17

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 2.13 (2H, tt, J=7.3, 7.6 Hz), 2.70(1H, t, J=7.6 Hz), 4.36 (2H, s), 4.58 (2H, t, J=7.3 Hz), 7.15-7.24 (5H,m), 7.38-7.44 (3H, m), 7.57 (1H, m), 7.82 (1H, m), 7.96 (1H, m), 8.13(1H, s), 8.98 (1H, s), 15.14 (1H, brs)

MS (ESI): M+ 465

EXAMPLE 1-18

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.89 (6H, d, J=6.7 Hz), 2.16 (1H, tq,J=6.7, 7.6 Hz), 4.37 (2H, s), 4.39 (2H, d, J=7.6 Hz), 7.38-7.47 (2H, m),7.58 (1H, m), 7.83 (1H, dd, J=2.0, 8.9 Hz), 8.02 (1H, d, J=8.9 Hz), 8.14(1H, d, J=2.0 Hz), 8.97 (1H, s), 15.15 (1H, brs)

MS (ESI): M+ 403

EXAMPLE 1-19

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 1.61-1.64(2H, m), 1.76-1.84(2H, m),2.60(2H, t, J=7.5 Hz), 4.36(2H, s), 4.56(2H, t, J=7.2 Hz), 7.15-7.17(3H,m), 7.22-7.24(2H, m), 7.38-7.40(1H, m), 7.44(1H, m), 7.56-7.59(1H, m),7.82(1H, d, J=2 Hz), 7.96(1H, d, J=8.9 Hz), 8.14(1H, d, J=1.8 Hz),9.01(1H, s), 15.15(1H, brs)

MS (ESI): M+ 514

EXAMPLE 1-20

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 4.28(2H, s), 5.73(2H, s), 7.02(1H, d,J=7.6 Hz), 7.27-7.43(11H, m), 7.55(1H, d, J=7.6 Hz), 7.60-7.62(1H, m),8.08(1H, d, J=1.6 Hz), 8.92(1H, s), 14.97(1H, brs)

MS (ESI): M+ 502

EXAMPLE 1-21

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 1.45-1.49(2H, m), 1.81-1.85(2H, m),3.42(2H, t, J=6.3 Hz), 4.36(2H, s), 4.56(2H, t, J=7.4 Hz), 7.38(1H, dd,J=7.7, 7.8 Hz), 7.44-7.46(1H, m), 7.57(1H, dd, J=1.4, 7.8 Hz), 7.83(1H,dd, J=2.0, 8.8 Hz), 8.0(1H, d, J=8.9 Hz), 8.14(1H, d, J=1.8 Hz),9.01(1H, s), 15.18(1H, brs)

MS (ESI): M+ 420

EXAMPLE 1-22

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 4.32(2H, s), 6.16(2H, s),7.32-7.42(4H, m), 7.51-7.55(2H, m), 7.77-7.89(3H, m), 8.06-8.12(2H, m),9.31(1H, s), 15.02(1H, brs)

MS (ESI): M+ 494

EXAMPLE 1-23

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 4.31(2H, s), 5.83(2H, s),7.19-7.21(1H, m), 7.33-7.43(2H, m), 7.54-7.59(2H, m), 7.68-7.79(3H, m),8.12(1H, s), 9.25(1H, s), 15.05(1H, brs)

MS (ESI): M+ 508

EXAMPLE 1-24

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 2.18(6H, s), 2.64(2H, br), 4.36(2H,s), 4.63(2H, br), 7.38-7.40(1H, m), 7.45(1H, d, J=1.3 Hz), 7.56-7.58(1H,m), 7.84(1H, m), 8.00(1H, d, J=8.9 Hz), 8.14(1H, d, J=1.7 Hz), 8.90(1H,s), 15.15(1H, brs)

MS (ESI): M+ 419

EXAMPLE 1-25

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 1.93-1.98(2H, m), 3.45(2H, t, J=5.6Hz), 4.36(2H, s), 4.59(2H, t, J=7.0 Hz), 4.68(1H, br), 7.37(1H, dd,J=7.7, 7.8 Hz), 7.44-7.468(1H, m), 7.57(1H, d, J=7.8 Hz), 7.83-7.99(1H,m), 8.00(1H, d, J=8.9 Hz), 8.14(1H, s), 8.96(1H, s), 15.16(1H, brs)

MS (ESI): M+ 406

EXAMPLE 1-26

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.21(3H, s), 3.70(2H, t, J=4.8 Hz),4.36(2H, s), 4.75(2H, t, J=4.8 Hz), 7.38(1H, dd, J=7.7, 7.7 Hz),7.44-7.47(1H, m), 7.58(1H, dd, J=1.6, 7.8 Hz), 7.83(1H, dd, J=2.1, 8.9Hz), 8.04(1H, d, J=8.9 Hz), 8.14(1H, d, J=2.0 Hz), 8.89(1H, s),15.14(1H, brs)

MS (ESI): M+ 406

EXAMPLE 1-27

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 4.36(2H, s), 5.68(2H, q, J=8.7 Hz),7.38(1H, dd, J=7.7, 7.7 Hz), 7.46(1H, dd, J=1.7, 7.7 Hz), 7.89(1H, dd,J=2.1, 8.9 Hz), 8.13-8.16(2H, m), 9.11(1H, s), 14.71(1H, brs)

MS (ESI): M+ 430

EXAMPLE 1-28

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 4.34(2H, s), 4.78(2H, s),7.34-7.44(2H, m), 7.55-7.57(1H, m), 7.69(1H, d, J=8.7 Hz), 7.76(1H, d,J=9.0 Hz), 8.09(1H, s), 8.85(1H, s), 15.37(1H, brs)

MS (ESI): M+ 406

EXAMPLE 1-29

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 2.04(3H, s), 3.27-3.38(2H, m),4.37(2H, s), 4.78(2H, t, J=6.8 Hz), 7.37-7.39(1H, m), 7.45-7.47(1H, m),7.58-7.61(1H, m), 7.85-7.87(1H, m), 8.03-8.05(1H, m), 8.15(1H, s),8.73(1H, s), 8.81(1H, s)

MS (ESI): M+ 473

EXAMPLE 1-30

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 1.20(3H, d, J=6.2 Hz), 3.96(1H, br),4.15-4.23(1H, m), 4.36(2H, s), 4.65-4.69(1H, m), 5.02(1H, br), 7.37(1H,dd, J=7.7, 8.0 Hz), 7.45(1H, d, J=6,6 Hz), 7.57(1H, d, J=8.1 Hz),7.81(1H, d, J=8.8 Hz), 8.03(1H, d, J=9.1 Hz), 8.13(1H, s), 8.84(1H, s)

MS (ESI): M+ 406

EXAMPLE 1-31

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.75 (2H, m), 4.19 (2H, s), 4.61 (2H,m), 5.00 (1H, br), 7.27-7.40 (4H, m), 7.86 (1H, m), 8.02 (1H, m), 8.26(1H, m), 8.86 (1H, s), 15.29 (1H, s)

MS (ESI): M+ 357

EXAMPLE 1-32

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 2.10(3H, s), 2.95(2H, t, J=6.6 Hz),4.37(2H, s), 4.76(2H, t, J=6.6 Hz), 7.38(1H, dd, J=7.7, 7.8 Hz),7.45-7.47(1H, m), 7.58(1H, dd, J=1.5, 7.9 Hz), 7.90(1H, dd, J=2.0, 8.9Hz), 8.00(1H, d, J=8.9 Hz), 8.15(1H, d, J=1.8 Hz), 9.02(1H, s),15.12(1H, brs)

MS (ESI): M+ -422

EXAMPLE 1-33

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.75(2H, s), 4.33(2H, s), 4.60(2H, t,J=4.8 Hz), 4.98(1H, br), 7.30-7.33(1H, m), 7.39-7.42(2H, m), 7.80(1H,dd, J=1.7, 8.9 Hz), 8.02(1H, d, J=8.9 Hz), 8.09(1H, s), 8.85(1H, s),15,14(1H, brs)

MS (ESI): M+ 375

EXAMPLE 1-34

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 1.33-1.44(4H, m), 1.75-1.81(2H, m),3.36-3.38(2H, m), 4.54(2H, t, J=7.2 Hz), 7.38(1H, dd, J=7.7, 7.7 Hz),7.46(1H, d, J=6.1 Hz), 7.57(1H, d, J=7.8 Hz), 7.83(1H, d, J=8.7 Hz),8.00(1H, d, J=8.9 Hz), 8.14(1H, s), 9.01(1H, s), 15.19(1H, brs)

MS (ESI): M+ 434

EXAMPLE 1-35

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 2.33-2.45(4H, br), 2.64(2H, t, J=6.2Hz), 3.52(2H, t, J=4.4 Hz), 4.27(2H, s), 4.40(2H, br), 7.34-7.42(2H, m),7.55-7.60(2H, m), 7.71(1H, d, J=8.6 Hz), 8.04(1H, s), 8.57(1H, s)

MS (ESI): M+ 461

EXAMPLE 1-36

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 4.08(3H, s), 4.37(2H, s), 7.37(1H, dd,J=7.7, 7.7 Hz), 7.44-7.46(1H, m), 7.57(1H, dd, J=1.7, 7.8 Hz),7.84-7.87(1H, m), 7.92(1H, d, J=8.8 Hz), 8.12(1H, s), 9.01(1H, s),15.20(1H, brs)

MS (ESI): M+ 362

EXAMPLE 1-37

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 1.41(3H, t, J=7.1 Hz), 4.36(2H, s),4.58(2H, q, J=7.1 Hz), 7.38(1H, dd, J=7.8, 7.7 Hz), 7.44-7.46(1H, m),7.57(1H, dd, J=1.5, 7.9 Hz), 7.83(1H, dd, J=2.1, 8.8 Hz), 8.01(1H, d,J=8.8 Hz), 8.14(1H, s), 9.02(1H, s), 15.18(1H, brs)

MS (ESI): M+ 376

EXAMPLE 1-38

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.90(3H, t, J=7.3 Hz), 1.77-1.85(2H,m), 4.36(2H, s), 4.51(2H, t, J=7.3 Hz), 7.38(1H, dd, J=7.8, 7.6 Hz),7.44-7.46(1H, m), 7.58(1H, dd, J=1.7, 7.8 Hz), 7.83(1H, dd, J=2.1, 8.8Hz), 8.02(1H, d, J=8.9 Hz), 8.14(1H, d, J=2.0 Hz), 9.02(1H, s),15.18(1H, brs)

MS (ESI): M+ 390

EXAMPLE 1-39

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.90(3H, t, J=7.3 Hz), 1.30-1.37(2H,m), 1.74-1.79(2H, m), 4.36(2H, s), 4.54(2H, t, J=7.3 Hz), 7.38(1H, dd,J=7.6, 7.8 Hz), 7.46(1H, dd, J=1.7, 7.6 Hz), 7.58(1H, dd, J=1.7, 7.8Hz), 7.83(1H, dd, J=2.1, 8.9 Hz), 8.00(1H, d, J=8.9 Hz), 8.14(1H, d,J=2.0 Hz), 9.01(1H, s), 15.18(1H, brs)

MS (ESI): M+ 404

EXAMPLE 1-40

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 1.27-1.29(2H, m), 1.47-1.50(2H, m),1.59-1.66(4H, m), 2.31-2.40(1H, m), 4.36(2H, s), 4.51(2H, d, J=7.6 Hz),7.38-7.47(2H, m), 7.57(1H, dd, J=1.5, 7.8 Hz), 7.82(1H, dd, J=2.0, 8.8Hz), 8.05(1H, d, J=8.9 Hz), 8.14(1H, d, J=1.8 Hz), 9.028(1H, s),15.16(1H, brs)

MS (ESI): M+ 430

EXAMPLE 1-41

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.11(3H, s) 3.77(2H, t), 4,37(2H, s),4.99(2H, t), 7.35-7.41(1H, m), 17.47(1H, d), 7.58(1H, d, J=7.8 Hz),7.83-7.92(2H, m), 8.16(1H, s), 9.05(1H, s)

MS (ESI).: M+ 454

EXAMPLE 1-42

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 1.10(4H, br), 1.54-1.65(4H, br),1.83(1H, br), 4.36(2H, s), 4.40(2H, d, J=7.4; Hz), 7.38(1H, dd, J=7.7,7.8 Hz), 7.45-7.48(1H, m), 7.58(1H, dd, J=1.6, 7.8 Hz), 7.81-7.84(1H,m), 8.02(1H, d, J=8.9 Hz), 8.13(1H, s), 8.93(1H, s), 15.17(1H, brs)

MS (ESI): M+ 444

EXAMPLE 1-43

¹H NMR (DMSO-d₆ 300 MHZ) (δ) ppm: 4.37(2H, s), 4.49-4.56(1H, m),4.77-4.82(1H, m), 4.91-4.97(1H, m), 5.81(1H, d, J=4.7 Hz), 7.30-760(8H,m), 7.81(1H, d, J=11.0 Hz), 8.08(1H, d, J=8.9 Hz), 8.17(1H, d), 8.93(1H,s), 15.19(1H, brs)

MS (ESI): M+ 468

EXAMPLE 1-44

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 4.37(2H, s), 4.72-4.76(1H, m),4.92(2H, t, J=4.6 Hz), 4.98-5.01(1H, m), 7.38(1H, dd, J=7.8, 8.1 Hz),7.44-7.46(1H, m), 7.58(1H, dd, J=1.6, 7.9 Hz), 7.84(1H, dd, J=2.1, 9.0Hz), 8.03(1H, d, J=9.3 Hz), 8.15(1H, d, J=1.8 Hz), 8.78(1H, s), 8.98(1H,s)

MS (ESI): M+ 394

EXAMPLE 1-45

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.21(2H, br), 4.27(2H, s), 4.65(2H,br), 7.20-7.28(2H, m), 7.33-7.41(2H, m), 7.54-7.70(5H, m), 7.77(1H, d,J=8.7 Hz), 8.05(1H, s), 8.50(1H, s), 8.52(1H, s)

MS (ESI): M+ 453

EXAMPLE 1-46

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 2.93(2H, t), 4.35(2H, s), 4.48(2H, s),7.38(1H, dd, J=7.7, 7.7 Hz), 7.45(1H, d, J=6.2 Hz), 7.57(1H, d, J=7.7Hz), 7.82(1H, d), 8.02(1H, d, J=9.1 Hz), 8.13(1H, s), 8.92(1H, s)

MS (ESI): M+ 391

EXAMPLE 1-47

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 1.13(6H, s), 4.35(2H, s), 4.50(2H, s),4.90(1H, brs), 7.35-7.46(2H, m), 7.57(1H, d, J=7.7 Hz), 7.78(1H, d,J=7.1 Hz), 8.10(1H, s), 8.19(1H, d, J=9.0 Hz), 8.88(1H, s), 15.22(1H,brs)

MS (ESI): M+ 420

EXAMPLE 1-48

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 1.68(3H, s), 3.46(2H, br) 4.36(2H, s),4.56(2H, br), 7.38-7.60(3H, m), 7.81-8.13(4H, m), 8.80(1H, s)

MS (ESI): M+ 433

EXAMPLE 1-49

¹H NMR (DMSO- d₆ 300 MHz) (δ) ppm: 1.00(3H, t, J=7.0 Hz), 3.41(2H, br),3.82(2H, q), 4.36(2H, s), 4.57(2H, br), 7.24(1H, m), 7.38(1H, m),7.46(1H, m), 7.58(1H, m), 7.83(1H, m), 8.03(1H, m), 8.13(1H, s),8.82(1H, s)

MS (ESI): M+ 463

EXAMPLE 1-50

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.75(2H, m), 4.26(2H, s), 4.61(2H, t,J=4.8 Hz), 5.00(1H, br), 7.17-7.36(3H, m), 7.83(1H, dd, J=2.0, 8.8 Hz),8.03(1H, d, J=8.9 Hz), 8.21(1H, s), 8.87(1H, s), 15.22(1H, brs)

MS (ESI): M+ 360

EXAMPLE 1-51

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.75(2H, m), 4.28(2H, s), 4.61(2H, t,J=4.8 Hz), 5.00(1H, br), 7.24-7.28(1H, m), 7.44-7.55(2H, m), 7.80(1H,dd, J=2.1, 8.8 Hz), 8.02(1H, d, J=8.9 Hz), 8.13(1H, d, J=1.9 Hz),8.86(1H, s), 15.22(1H, s)

MS (ESI): M+ 376

EXAMPLE 1-52

¹H NMR (CDCl₃ 300 MHz) (δ) ppm: 1.42(3H, t, J=7.1 Hz), 4.05(2H, s),4.40(2H, q, J=7.1 Hz), 5.35(2H, s), 7.13-7.28(8H, m), 7.33-7.35(2H, m),8.41(1H, d, J=2.0 Hz), 8.58(1H, s)

MS (ESI): M+ 398

EXAMPLE 1-53

¹H NMR (CDCl₃ 300 MHz) (δ) ppm: 4.10(2H, s), 5.48(2H, s), 7.13-7.50(12H,m), 8.41(1H, d, J=1.9 Hz), 8.87(1H, s), 14.96(1H, brs)

MS (ESI): M+ 370

EXAMPLE 1-54

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 4.16(2H, s), 5.44(2H, s),7.19-7.34(5H, m), 7.74(1H, d, J=8.8 Hz), 7.83(1H, dd, J=2.0, 8.9 Hz),8.22(1H, d, J=1.9 Hz), 9.08(1H, s), 13.58(1H, brs), 15.13(1H, brs)

MS (ESI): M+ 338

EXAMPLE 1-55

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.89(3H, t, J=7.3 Hz), 1.25-1.35(5H,m), 1.66-1.76(2H, m), 4.09(2H, s), 4.21(2H, q, J=7.1 Hz), 4.34(2H, t,J=7.2 Hz), 7.20-7.33(5H, m), 7.66(1H, dd, J=2.1, 8.7 Hz), 7.74(1H, d,J=8.7 Hz), 8.06(1H, d, J=1.9 Hz), 8.64(1H, s)

MS (ESI): M+ 364

EXAMPLE 1-56

¹H NMR (CDCl₃ 300 MHz) (δ) ppm: 0.99(3H, t, J=7.3 Hz), 1.43(2H, m),1.84-1.94(2H, m), 4.15(2H, s), 4.28(2H, t, J=7.4 Hz), 7.20-7.34(5H, m),7.52(1H, d, J=8.8 Hz), 7.65(1H, dd, J=2.1, 8.8 Hz), 8.42(1H, d, J=1.9Hz), 8.72(1H, s), 15.04(1H, brs)

MS (ESI): M+ 336

EXAMPLE 1-57

¹H NMR (CDCl₃ 300 MHz) (δ) ppm: 1.41(3H, t, J=7.2 Hz), 3.85(3H, s),4.11(2H, s), 4.39(2H, q, J=7.2 Hz), 7.17-7.35(6H, m), 7.51(1H, dd,J=2.4, 8.4 Hz), 8.42(1H, d, J=1.8 Hz), 8.45(1H, s)

MS (ESI): M+ 322

EXAMPLE 1-58

¹H NMR (CDCl₃ 300 MHz) (δ) ppm: 3.99(3H, s), 4.16(2H, s), 7.19-7.33(5H,m), 7.52(1H, d, J=8.7 Hz), 7.68(1H, dd, J=2.0, 8.7 Hz), 8.41(1H, s),8.72(1H, s)

MS (ESI): M+ 294

EXAMPLE 1-59

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 2.08-2.15(2H, m), 2.69(2H, t, J=7.8Hz), 4.16(2H, s), 4.57(2H, t, J=7.3 Hz), 7.15-7.31(10H, m), 7.81(1H, dd,J=2.0, 8.8 Hz), 7.92(1H, d, J=8.8 Hz), 8.20(1H, d, J=1.9 Hz), 8.96(1H,s), 15.21(1H, brs)

MS (ESI): M+ 398

EXAMPLE 1-60

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.11(2H, t, J=7.3 Hz), 4.18(2H, s),4.77(2H, t, J=7.4 Hz), 7.19-7.35(10H, m), 7.86(1H, d, J=8.7 Hz),8.06(1H, d, J=8.8 Hz), 8.22(1H, s), 8.76(1H, s), 15.14(1H, brs)

MS (ESI): M+ 384

EXAMPLE 1-61

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 1.99-2.03(2H, m), 2.37(2H, t, J=7.1Hz), 4.17(2H, s), 4.54(2H, t, J=7.3 Hz), 7.21-7.34(5H, m), 7.87(1H, dd,J=2.0, 8.8 Hz), 8.05(1H, d, J=8.8 Hz), 8.21(1H, d, J=1.9 Hz), 8.98(1H,s), 12.01(1H, brs), 15.28(1H, brs)

MS (ESI): M+ 366

EXAMPLE 1-62

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 4.15(2H, s), 5.48(2H, s),7.06-7.10(1H, m), 7.20-7.22(1H, m), 7.28-7.34(6H, m), 7.56-7.58(2H, m),7.74(1H, d, J=8.8 Hz), 7.848.9 Hz), 8.23(1H, s), 9.10(1H, s), 10.63(1H,brs), 15.18(1H, brs)

MS (ESI): M+ 413

EXAMPLE 1-63

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.72 (2H, m), 4.26 (2H, s), 4.35 (2H,m), 5.23 (1H, br), 7.32-7.41 (2H, m), 7.53-7.58 (2H, m), 7.72 (1H, m),8.05 (1H, s), 8.63 (1H, s)

MS (ESI): M+ 391

EXAMPLE 1-64

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.72 (2H, m), 4.23 (2H, s), 4.35 (2H,m), 5.24 (1H, br), 7.25-7.40 (3H, m), 7.57 (1H, m), 7.72 (1H, m), 8.03(1H, s), 8.63 (1H, s)

MS (ESI): M+ 375

EXAMPLE 1-65

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.12 (2H, t, J=7.3 Hz), 4.31 (2H, s),4.78 (2H, t, J=7.3 Hz), 7.20-7.36 (7H, m), 7.46-7.48 (2H, m), 7.86 (1H,m), 8.09 (1H, m), 8.15 (1H, s), 8.78 (1H, s), 15.08 (1H, brs)

MS (ESI): M+ 417

EXAMPLE 1-66

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.79 (2H, m), 4.39 (2H, s), 4.65 (2H,m), 5.04 (1H, m), 7.31-7.47 (3H, m), 7.88 (1H, m), 8.07 (1H, m), 8.19(1H, m), 8.90 (1H, s), 15.25 (1H, s)

MS (ESI): M+ 375

EXAMPLE 1-67

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.74 (2H, m), 4.35 (2H, s), 4.62 (2H,m), 5.00 (1H, br), 7.62 (1H, m), 7.81 (1H, m), 7.90 (1H, m), 8.02-8.13(2H, m), 8.23 (1H, m), 8.32 (1H, m), 8.87 (1H, s)

MS (ESI): M+ 368

EXAMPLE 1-68

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 2.09 (3H, s), 4.35 (2H, s), 5.75 (2H,s), 7.37 (1H, m), 7.44. (1H, m), 7.55. (1H, m), 7.83 (1H, m), 8.01 (1H,m), 8.12 (1H, m), 9.10 (1H, s)

MS (ESI): M+ 407

EXAMPLE 1-69

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.20 (3H, s) 4.36 (2H, s), 6.22 (2H,s), 7.36-7.47 (2H, m), 7.58 (1H, m), 7.86 (1H, m), 8.12-8.15 (2H, m),9.04 (1H, s)

MS (ESI): M+ 439

EXAMPLE 1-70

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 1.22 (9H, s), 4.36 (2H, s), 5.99 (2H,s), 7.35-7.46 (3H, m), 7.58 (1H, m), 7.84 (1H, m), 8.08-8.11 (2H, m),8.95 (1H, s), 14.75 (1H, br)

MS (ESI): M+ 496

EXAMPLE 1-71

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 2.62 (3H, d, J=4.7 Hz), 4.36 (2H, s),6.11 (2H, s), 7.36-7.47 (2H, m), 7.54-7.60 (2H, m), 7.84 (1H, m),8.10-8.13 (2H, m), 8.98 (1H, s), 14.79 (1H, br)

MS (ESI): M+ 454

EXAMPLE 1-72

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 2.77 (6H, s), 4.37 (2H, s), 6.20 (2H,s), 7.39 (1H, dd, J=7.8, 7.8 Hz), 7.47 (1H, dd, J=1.7, 7.8 Hz), 7.59(1H, dd, J=1.7, 7.8 Hz), 7.89 (1H, m), 8.11-8.14 (2H, m), 9.04 (1H, s),14.69 (1H, br)

MS (ESI): M+ 468

EXAMPLE 1-73

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.75 (2H, br), 4.36 (2H, s), 4.60 (2H,m), 5.00 (1H, br), 7.39-7.49 (2H, m), 7.82 (1H, m), 8.04 (1H, m), 8.11(1H, s), 8.87 (1H, s), 15.14 (1H, brs)

MS (ESI): M+ 393

EXAMPLE 1-74

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.41 (1H, m), 3.51 (1H, m) 3.82 (1H,m), 4.26 (1H, m), 4.36-(2H, s), 4.79 (1H, m), 4.93 (1H, m), 5.19 (1H,m), 7.38 (1H, m), 7.46 (1H, m), 7.58 (1H, m), 7.84 (1H, m), 7.97 (1H,m), 8.15 (1H, m), 8.84 (1H, s)

MS (ESI): M+ 421

EXAMPLE 1-75

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 4.32 (2H, s), 5.98 (2H, s), 7.31-7.43(5H, m), 7.80 (1H, m), 8.06 (1H, m), 8.12 (1H, m), 8.99 (1H, m), 14.81(1H, brs)

MS (ESI): M+ 424

EXAMPLE 1-76

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 2.62 (3H, d, J=4.4 Hz), 4.32 (2H, s),6.11 (2H, s), 7.30-7.43 (3H, m), 7.53 (1H, q, J=4.4 Hz), 7.84 (1H, m),8.06 (1H, s), 8.12 (1H, m), 8.98 (1H, m), 14.74 (1H, s)

MS (ESI): M+ 438

EXAMPLE 1-77

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 2.77 (6H, s), 4.33 (2H, s), 6.19 (2H,s), 7.27-7.44 (3H, m), 7.89 (1H, m), 8.06-8.14 (2H, m), 9.03 (1H, s),14.64 (1H, s)

MS (ESI): M+ 452

EXAMPLE 1-78

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.74 (2H, dt, J=4.8, 5.6 Hz), 4.17(2H, s), 4.60 (2H, t, J=4.8 Hz), 4.99 (1H, t, J=5.6 Hz), 7.20-7.32 (5H,m), 7.82 (1H, m), 7.99 (1H, m), 8.21 (1H, m), 8.84 (1H, s), 15.27 (1H,s)

MS (ESI): M+ 323

EXAMPLE 1-79

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 2.34 (3H, s), 3.75 (2H, br), 4.30 (2H,s), 4.61 (2H, t, J=4.7 Hz), 5.00 (1H, br), 7.21-7.31 (3H, m), 7.81 (1H,dd, J=2.0, 8.9 Hz), 8.01 (1H, d, J=8.9 Hz), 8.15 (1H, d, J=2.0 Hz), 8.86(1H, s), 15.23 (1H, s)

MS (ESI): M+ 371

EXAMPLE 1-80

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.76 (2H, m), 4.31 (2H, s), 4.61 (2H,m), 5.01 (1H, m), 7.23 (1H, m), 7.36-7.47 (2H, m), 7.65 (1H, m), 7.81(1H, m),8.02 (1H, m), 8.14 (1H, m), 8.86 (1H, s)

MS (ESI): M+ 401

EXAMPLE 1-81

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 2.26 (3H, s), 3.75 (2H, m), 4.12 (2H,s), 4.60 (2H, m), 4.99 (1H, m), 7.10-7.18 (4H, m), 7.80 (1H, m), 7.99(1H, m), 8.20 (1H, m), 8.85 (1H, s), 15.29 (1H, s)

MS (ESI): M+ 337

EXAMPLE 1-82

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.73 (2H, dt, J=4.8, 5.2 Hz), 3.84(3H, s), 4.28 (2H, s), 4.60 (2H, t, J=4.8 Hz), 5.00 (1H, t, J=5.2 Hz),7.04-7.07 (2H, m), 7.30 (1H, m), 7.79 (1H, m), 8.00 (1H, m), 8.11 (1H,m), 8.84 (1H, s), 15.22 (1H, s)

MS (ESI): M+ 387

EXAMPLE 1-83

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.75 (2H, m), 4.50 (2H, s), 4.62 (2H,m), 7.60-8.15 (5H, m), 8.35 (1H, s), 8.68 (1H, m), 8.87 (1H, s), 15.25(1H, br)

MS (ESI): M+ 324

EXAMPLE. 1-84

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.75 (2H, m), 4.33 (2H, s), 4.62- (2H,m), 7.57 (2H, d, J=6.3 Hz), 7.89 (1H, dd, J=2.1, 8.7 Hz), 8.07 (1H, d,J=8.7 Hz), 8.32 (1H, d, J=2.1 Hz), 8.62 (1H, d, J=6.3 Hz), 8.88 (2H, s)

MS (ESI): M+ 324

EXAMPLE 1-85

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.21 (3H, s), 3.77 (2H, m), 4.61 (2H,m), 4.66 (2H, s), 5.02 (1H, m), 7.38 (1H, m), 7.55 (1H, m), 7.68 (1H,m), 7.81 (1H, m), 8.00-8.05 (2H, m), 8.19 (1H, m), 8.87 (1H, s)

MS (ESI): M+ 401

EXAMPLE 1-86

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.73 (2H, m), 4.15 (2H, s), 4.58 (2H,m), 5.00 (1H, m), 7.23-7.50 (10 H, m), 7.88-7.92 (2H, m), 8.83 (1H, s)

MS (ESI): M+ 399

EXAMPLE 1-87

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.75 (2H, m), 4.30 (2H, s), 4.61 (2H,m), 5.00 (1H, br), 7.26-7.38 (2H, m), 7.43-7.49 (2H, m), 7.82 (1H, m),8.02 (1H, m), 8.14 (1H, m0, 8.86 (1H, s), 15.32 (1H, s)

MS (ESI): M+ 357

EXAMPLE 1-88

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.74 (2H, m), 4.25 (2H, s), 4.60 (2H,m), 4.98 (1H, br), 7.25-7.53 (6H, m), 7.59-7.66 (3H, m), 7.87 (1H, m),8.10 (1H, m), 8.29 (1H, m), 8.85 (1H, s), 15.30 (1H, s)

MS (ESI): M+ 399

EXAMPLE 1-89

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.79 (2H, m), 4.33 (2H, s), 4.64 (2H,m), 5.03 (1H, m), 7.57-7.65 (3H, m), 7.76 (1H, m), 7.91 (1H, m), 8.06(1H, m), 8.32 (1H, m), 8.90 (1H, s), 15.31 (1H, s)

MS (ESI): M+ 391

EXAMPLE 1-90

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 1.30 (3H, t, J=6.8 Hz), 3.74 (2H, m),3.98 (2H, q, J=6.8 Hz), 4.12 (2H, s), 4.60 (2H, m), 5.01 (1H, m), 6.76(1H, m), 6.82-6.84 (2H, m), 7.20 (1H, m), 7.82 (1H, m), 7.99 (1H, m),8.22 (1H, m), 8.85 (1H, s) MS (ESI): M+ 367

EXAMPLE 1-91

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.75 (2H, m), 4.25 (2H, s), 4.61 (2H,m), 7.53 (1H, m), 7.66-7.71 (2H, m), 7.83-7.89 (2H, m), 8.02 (1H, m),8.28 (1H, m), 8.87 (1H, s)

MS (ESI): M+ 348

EXAMPLE 1-92

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 2.48 (3H, m), 3.74 (2H, m), 4.26 (2H,s), 4.61 (2H, m), 5.09 (1H, br), 7.19 (1H, m), 7.39 (2H, m), 7.82 (1H,m), 8.04 (1H, m), 8.13 (1H, s), 8.85 (1H, s), 15.22 (1H, s)

MS (ESI): M+ 403

EXAMPLE 1-93

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.75 (2H, m), 4.24 (2H, s), 4.61 (2H,m), 5.02 (1H, br), 7.38-7.47 (4H, m), 7.80 (1H, m), 8.03 (1H, m), 8.16(1H, m), 8.86 (1H, s), 15.23 (1H, s)

MS (ESI): M+ 407

EXAMPLE 1-94

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.76 (2H, m), 3.99 (2H, s) 4.61 (2H,m), 5.01 (3H, m), 6.41 (3H, m), 6.93 (1H, m), 7.78 (1H, m), 8.00 (1H,m), 8.20 (1H, m), 8.86 (1H, s)

MS (ESI): M+ 338

EXAMPLE 1-95

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 1.00 (3H, s), 3.76 (2H, m), 4.13 (2H,s), 4.61 (2H, m), 5.01 (1H, m), 6.98 (1H, m), 7.23 (1H, m), 7.43 (2H,m), 7.81 (1H, m), 8.01 (1H, m), 8.21 (1H, m), 8.86 (1H, s), 9.87 (1H, s)

MS (ESI): M+ 380

EXAMPLE 1-96

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.73 (2H, m), 4.18 (2H, s), 4.59 (2H,m), 4.98 (1H, br), 7.26 (1H, s), 7.29 (1H, m), 7.39 (1H, m), 7.53 (1H,m), 7.99 (1H, s), 8.24 (1H, m), 8.85 (1H, s), 15.25 (1H, s)

MS (ESI): M+ 401

EXAMPLE 1-97

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 2.28 (3H, s), 3.75 (2H, m), 4.25 (2H,s), 4.61 (2H, m), 5.04 (1H, br), 7.13 (1H, s), 7.29-7.36 (2H, m), 7.81(1H, m), 8.03 (1H, m), 8.13 (1H, s), 8.86 (1H, s), 15.24 (1H, s)

MS (ESI): M+ 371

EXAMPLE 1-98

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 2.59 (6H, s), 3.75 (2H, m), 4.33 (2H,s), 4.61 (2H, m), 5.00 (1H, m), 7.59-7.64 (3H, m), 7.73 (1H, m), 7.87(1H, m), 8.03 (1H, m), 8.27 (1H, s), 8.86 (1H, s), 15.27 (1H, s)

MS (ESI): M+ 430

EXAMPLE 1-99

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.75 (2H, m), 4.26 (2H, s), 4.61 (2H,m), 5.00 (1H, br), 7.21 (1H, m), 7.38-7.51 (2H, m), 7.83 (1H, m), 8.03(1H, m), 8.22 (1H, s), 8.87 (1H, s)

MS (ESI): M+ 375

EXAMPLE 1-100

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.76 (2H, m), 4.26 (2H, s), 4.61 (2H,m), 4.99 (1H, m), 7.25 (1H, m), 7.61 (1H, m), 7.81 (1H, m), 8.04 (1H,m), 8.16 (1H, m), 8.87 (1H, s), 15.16 (1H, s)

MS (ESI): M+ 393

EXAMPLE 1-101

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.79(2H, m), 4.01(3H, s), 4.19(2H, s),4.64-4.65(2H, m), 5.02(1H, t, J=5.5 Hz), 7.25(1H, d, J=1.6 Hz),7.31-7.35(2H, m), 7.56-7.58(1H, m), 7.82(1H, s), 8.78(1H, s), 15.38(1H,brs)

MS (ESI): M+ 422

EXAMPLE 1-102

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 1.19 (2H, m), 1.30 (2H, m), 3.83 (1H,m), 4.37 (2H, s), 7.38 (1H, m), 7.46 (1H, m), 7.57 (1H, m), 7.89 (1H,m), 8.12 (1H, m), 8.24 (1H, m), 8.73 (1H, s), 15.05 (1H, s)

MS (ESI): M+ 387

EXAMPLE 2-1

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 4.37 (2H, s), 6.88 (2H, brs),7.35-7.47 (2H, m), 7.58 (1H, m), 7.87 (1H, dd, J=2.1, 8.9 Hz), 8.08 (1H,d, J=2.1 Hz), 8.16 (1H, d, J=8.9 Hz), 8.86 (1H, s), 15.24 (1H, brs)

MS (ESI): M+ 362

EXAMPLE 2-2

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.75 (3H, brs), 4.36 (2H, s), 7.35(1H, m), 7.42 (1H, m), 7.54 (1H, m), 7.72 (1H, m), 7.85 (1H, m), 8.10(1H, s), 9.03 (1H, s), 11.61 (1H, brs)

MS (ESI): M+ 420

EXAMPLE 2-3

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 2.16(3H, s), 4.36(2H, s),7.35-7.45(2H, m), 7.58(1H, dd, J=1.8, 7.8 Hz), 7.76-7.85(2H, m),8.10(1H, s), 8.96(1H, s), 12.02(1H, brs), 14.77(1H, brs)

MS (ESI): M+ 405

EXAMPLE 2-4

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.32 (3H, s), 4.37 (2H, s), 7.38 (1H,m), 7.46 (1H, m), 7.58 (1H, m), 7.86 (1H, m), 8.06-8.10 (2H, m), 8.82(1H, s), 14.60 (1H, br)

MS (ESI): M+ 440

EXAMPLE 2-5

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.46 (3H, s), 3.53 (3H, s), 4.37 (2H,s), 7.38 (1H, dd, J=7.8, 7.8 Hz), 7.47 (1H, dd, J=2.1, 7.8 Hz), 7.58(1H, dd, J=2.1, 7.8 Hz), 7.88 (1H, dd, J=1.8, 8.7 Hz), 7.97 (1H, d,J=8.7 Hz), 8.12 (1H, d, J=1.8 Hz), 9.11 (1H, s), 15.54 (1H, brs)

MS (ESI): M+ 454

EXAMPLE 2-6

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 2.96 (6H, s), 4.36 (2H, s), 7.38 (1H,dd, J=7.8, 7.8 Hz), 7.46 (1H, dd, J=2.0, 7.8 Hz), 7.57 (1H, dd, J=2.0,7.8 Hz), 7.86 (1H, dd, J=2.2, 8.8 Hz), 8.12 (1H, d, J=2.2 Hz), 8.25 (1H,d, J=8.8 Hz), 9.25 (1H, s), 15.14 (1H, brs)

MS (ESI): M+ 390

EXAMPLE 2-7

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 2.84 (3H, d), 4.35(2H, s), 7.19 (1H,q), 7.38 (1H, m), 7.45 (1H, m), 7.55 (1H, m), 7.85 (1H, m), 8.09-8.11(2H, m), 8.99 (1H, m)

MS (ESI): M+ 37-6

EXAMPLE 2-8

¹H NMR (DMSO-d₆ 300 MHz) (δ)ppm: 1.09 (3H, t, J=7.1 Hz), 3.13 (2H, dq,J=6.1, 7.1 Hz), 4.36 (2H, s), 7.19 (1H, t, J=6.1 Hz), 7.38 (1H, dd,J=7.7, 7.7 Hz), 7.46 (1H, dd, J=1.7, 7.7 Hz), 7.58 (1H, dd, J=1.7, 7.8Hz), 7.85 (1H, dd, J=2.1, 8.8 Hz), 8.10 (1H, d, J=2.1 Hz), 8.15 (1H, d,J=8.8 Hz), 8.99 (1H, s), 15.14 (1H, brs)

MS (ESI): M+ 390

EXAMPLE 3-1

¹H NMR (DMSO-d₆ 300 MHz) (δ)ppm: 3.75 (2H, m), 3.79 (3H, s), 4.28 (2H,s), 4.57 (2H, m), 5.02 (1H, m), 7.17 (1H, m), 7.32 (1H, m), 7.57 (2H,m), 7.76 (1H, m), 8.83 (1H, m), 15.75(1H, s)

MS (ESI): M+ 421

EXAMPLE 3-2

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 2.24 (3H, s), 3.77 (2H, dd, J=5.2, 5.6Hz), 4.27 (2H, s), 4.61 (2H, t, J=5.2 Hz), 5.05 (1H, t, J=5.6 Hz), 7.23(2H, m), 7.34 (1H, m), 7.76 (1H, m), 8.03 (1H, m), 8.08 (1H, m), 8.86(1H, s), 15.23(1H, s)

MS (ESI): M+ 371

EXAMPLE 3-3

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.73 (5H, s), 4.21 (2H, s), 4.61 (2H,t, J=4.8 Hz), 5.01 (1H, t, J=5.2 Hz), 5.02 (1H, m), 7.12 (1H, m), 7.25(1H, m), 7.37 (1H, m), 7.81 (1H, m), 8.01 (1H m), 8.19 (1H, m), 8.86(1H, s), 15.26 (1H, s)

MS (ESI): M+ 387

EXAMPLE 3-4

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.80 (2H, m), 4.01 (3H, s), 4.12 (2H,s), 4.65 (2H, m), 5.02 (1H, m), 7.17-7.50 (4H, m), 8.03 (1H, s), 8.81(1H, s), 15.45 (1H, s).

MS (ESI): M+ 405

EXAMPLE 3-5

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.74 (2H, t), 4.17 (2H, s), 4.56 (2H,t), 5.02 (1H, br), 7.20(1H, m), 7.31 (1H, m), 7.38 (1H, m), 7.52-7.56(2H, m), 8.86 (1H, s), 13.63 (1H, s)

MS (ESI): M+ 407

EXAMPLE 3-6

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.78 (2H, t), 4.18 (2H, s), 4.44-4.49(2H, m), 5.08 (1H, t), 7.20-7.25 (2H, m), 7.34-7.40 (1H, m), 7.56 (1H,d), 7.82 (1H, s), 8.77 (1H, s), 11.10-11.30 (1H, br), 15.49 (1H, s)

MS (ESI): M+ 408

EXAMPLE 3-7

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 2.68 (3H, d, J=4.4 Hz), 3.74 (2H, t,J=4.8 Hz), 4.04 (2H, s), 4.60 (2H, t, J=4.8 Hz), 5.01 (1H, t), 5.27 (1H,q, J=5.2 Hz), 6.51-6.56 (2H, m), 6.95 (1H, d), 7.07-7.09 (1H, m), 7.78(1H, d, J=9.2 Hz), 7.98 (1H, d, J=8.8 Hz), 8.21 (1H, s), 8.84 (1H, s),15.33 (1H, s)

MS (ESI): M+ 353

EXAMPLE 3-8

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 2.62 (6H, s), 3.74 (2H, t), 4.24 (2H,s), 4.60 (2H, t, J=4.8 Hz), 5.01 (1H, t), 6.97-7.05 (2H, m), 7.21 (2H,m), 7.77 (1H, d, J=11.2 Hz), 7.97 (1H, d), 8.16 (1H, s), 8.85 (1H, s),15.29 (1H, s)

MS (ESI): M+ 367

EXAMPLE 3-9

¹H NMR (DMSO-₆ 400 MHz) (δ) ppm: 4.35 (2H, s), 7.11 (1H, d, J=8.8HZ),7.37-7.40 (1H, m), 7.44 (1H, d), 7.56 (1H, d), 7.69-7.74 (6H, m), 8.19(1H, s), 8.68 (1H, s), 14.99 (1H, s)

MS (ESI): M+ 424

EXAMPLE 3-10

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.84-3.95 (4H, m), 4.36 (2H, s),5.11-5.19 (3H, m), 7.38 (1H, m), 7.45 (1H, d), 7.57 (1H, d), 7.82 (1H,d, J=9.2 Hz), 8.15 (1H, d, J=8.8 Hz), 8.90 (1H, s), 15.21 (1H, s)

MS (ESI): M+ 422

EXAMPLE 3-11

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.76 (2H, t), 4.05 (2H, s), 4.59 (2H,t), 5.00 (1H, t), 6.61 (1H, d), 6.64 (1H, s), 6.70 (1H, d, J=8.0 Hz),7.09-7.11 (1H, m), 7.81 (1H, d, J=8.8 Hz), 8.00 (1H, d, J=8.8 Hz), 8.21(1H, s), 8.86 (1H, s), 9.30 (1H, s), 15.30 (1H, s)

MS (ESI): M+ 340

EXAMPLE 3-12

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 1.80-1.90 (2H, m), 2.45-2.50 (2H, m),2.60-2.70 (2H, m), 4.36 (2H, s), 5.11-5.16 (1H, m), 7.38-7.40 (1H, m),7.45 (1H, d), 7.57 (1H, d), 7.81 (1H, d, J=8.8 Hz), 7.93 (1H, d), 8.14(1H, s), 8.68 (1H, s), 15.16 (1H, s)

MS (ESI): M+ 402

EXAMPLE 3-13

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 1.70-1.90 (4H, m), 1.91-2.00 (2H, m),2.20-2.30 (2H, m), 4.37 (2H, s), 5.20-5.30 (1H, m), 7.38-7.40 (1H, m),7.45 (1H, d), 7.57 (1H, d), 7.86 (1H, d), 8.16 (1H, d), 8.19 (1H, s),8.75 (1H, s), 15.16 (1H, s)

MS (ESI): M+ 416

EXAMPLE 3-14

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.70-3.80 (2H, m), 3.96 (3H, s), 4.32(2H, s), 4.81 (2H, t), 4.90 (1H, t), 7.35-7.43 (2H, m), 7.54-7.59 (2H,m), 7.69 (1H, s), 8.69 (1H, s),15.16 (1H, s)

MS (ESI): M+ 422

EXAMPLE 3-15

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 2.88 (3H, s), 2.95 (3H, s), 3.70-3.80(2H, m), 4.21 (2H, s), 4.61 (2H, t), 4.99 (1H, t), 7.20-7.23 (1H, m),7.33 (1H, s), 7.37-7.38 (2H, dx2), 7.86 (1H, d), 8.02 (1H, d, J=8.8 Hz),8.26 (1H, s), 8.86 (1H, s), 15.30 (1H, s)

MS (ESI): M+ 395

EXAMPLE 3-16

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 2.71 (6H, s), 3.70-3.76 (2H, m) 4.58(2H, s), 4.60 (2H, t, J=5.2 Hz), 5.02 (1H, t), 7.42 (1H, d), 7.51 (1H,m), 7.64 (1H, m), 7.80 (1H, d)I, 7.84 (1H, d), 8.01 (1H, d, J=8.8 Hz),8.11 (1H, s), 8.86 (1H, s), 15.25 (1H, s)

MS (ESI): M+ 431

EXAMPLE 3-17

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.73-3.75 (2H, m), 4.24 (2H, s), 4.61(2H, t), 5.00 (1H, t, J=5.6 Hz), 7.31 (1H, m), 7.48-7.51 (1H, m), 7.84(1H, d), 8.02 (1H, d), 8.21 (1H, s), 8.87 (1H, s), 15.22 (1H, s)

MS (ESI): M+ 394

EXAMPLE 3-18

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.70-3.80 (2H, m), 4.56 (2H, s), 4.60(2H, t), 5.00 (1H, t), 7.38-7.43 (2H, m), 7.52-7.54 (1H, m), 7.78 (1H,d), 7.87 (1H, d, J=7.8 Hz), 7.98 (1H, d, J=8.9 Hz), 8.11 (1H, s), 8.84(1H, s), 12.60-13.00 (1H, br), 15.29 (1H, s)

MS (ESI): M+ 368

EXAMPLE 3-19

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.74-3.77 (2H, m), 4.58 (2H, s), 4.61(2H, t), 5.02 (1H, t, J=5.6 Hz), 7.29 (1H, d), 7.46 (1H, m), 7.56 (1H,m), 7.70 (1H, m), 7.81 (1H, d), 7.87 (1H, d), 8.01 (1H, s), 8.18 (1H,s), 8.86 (1H, s), 15.27 (1H, s)

MS (ESI): M+ 417

EXAMPLE 3-20

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 1.37 (3H, t, J=6.9 Hz), 3.70-3.80 (2H,m), 4.22 (2H, s), 4.28 (2H, q, J=6.9 Hz), 4.65 (2H, t), 5.00 (1H, t),7.30-7.34 (3H, m), 7.60 (1H, d), 7.92 (1H, s), 8.80 (1H, s), 15.44 (1H,s)

MS (ESI): M+ 436

EXAMPLE. 3-21

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.76 (2H, m), 4.40 (2H, s), 4.63 (2H,t, J=5.1 Hz), 5.02 (1H, t, J=5.6 Hz) 7.20 (1H, d, J=6.3 Hz), 7.35-7.39(1H, m), 7.62 (1H, d, J=6.3 Hz), 8.00 (1H, s), 8.32 (1H, s), 8.89 (1H,s), 15.87 (1H, s)

MS (ESI): M+ 426

EXAMPLE 3-22

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.80 (2H, t, J=5.3 Hz), 4.48 (2H, s),4.75 (2H, t, J=4.6 Hz), 5.06 (1H, t, J=5.6 Hz), 7.24 (1H, d, J=6.3 Hz),7.39-7.42 (1H, m), 7.65 (1H, d, J=6.7 Hz), 7.95 (1H, s), 8.40 (1H, s),9.00 (1H, s), 14.62 (1H, s)

MS (ESI): M+ 460

EXAMPLE 3-23

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 1.53 (3H, d, J=6.4 Hz), 3.76-3.83 (2H,m), 4.26 (2H, s), 5.19-5.23 (2H, m), 7.20-7.22 (1H, m), 7.41-7.49 (2H,m), 7.86 (1H, d), 8.17 (1H, d, J=8.8 Hz), 8.24 (1H, s), 8.88 (1H, s)

MS (ESI): M+ 390

EXAMPLE 3-24

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 1.53 (3H, d, J=6.8 Hz), 3.76-3.82 (2H,m), 4.26 (2H, s), 5.19-5.23 (2H, m), 7.22-7.24 (1H, m), 7.41-7.49 (2H,m), 7.86 (1H, d), 8.17 (1H, d, J=9.2 Hz), 8.24 (1H, s), 8.88 (1H, s)

MS (ESI): M+ 390

EXAMPLE 3-25

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.40-3.50 (2H, m), 4.34 (2H, s), 4.57(2H, t), 4.89 (1H, t), 7.24-7.27 (1H, m), 7.45-7.51 (2H, m), 8.35 (1H,s), 8.45 (1H, s), 9.00 (1H, s), 14.30-14.40 (1H, br)

MS (ESI): M+ 444

EXAMPLE 3-26

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.84-3.96 (4H, m), 4.26 (2H, s),5.13-5.18 (3H, m), 7.19-7.21 (1H, m), 7.40-7.48 (2H, m), 7.84 (1H, d,J=9.2 Hz), 8.15 (1H, d, J=8.8 Hz), 8.23 (1H, s), 8.90 (1H, s), 15.24(1H, s)

MS (ESI): M+ 406

EXAMPLE 3-27

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.77 (2H, t, J=5.2 Hz), 4.53 (2H, s),4.68 (2H, t, J=4.8 Hz), 5.01 (1H, t, J=5.16 Hz), 7.32 (1H, d, J=6.0 Hz),7.39-7.43 (1H, m), 7.64 (1H, d, J=6.4 Hz), 8.07. (1H, s), 8.79 (1H, s),8.96 (1H, s), 14.61 (1H, s)

MS (ESI): M+ 417

EXAMPLE 3-28

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.97 (3H, t, J=7.2 Hz), 2.58 (3H, s),2.84 (2H, q, J=7.2 Hz), 3.77 (2H, t), 4.21 (2H, s), 4.60 (2H, t), 5.00.(1H, t), 7.00-7.02 (1H, m), 7.12 (1H, d), 7.20-7.24. (2H, m), 7.78 (1H,d, J=8.8 Hz), 7.98 (1H, d, J=8.8 Hz), 8.17 (1H, s), 8.84 (1H, s), 15.31(1H, s)

MS (ESI): M+ 381

EXAMPLE 3-29

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.78 (3H, t, J=7.2 Hz), 1.42 (2H, m),2.56 (3H, s), 2.76 (2H, t, J=6.8 Hz), 3.74 (2H, t), 4.23 (2H, s), 4.60(2H, t, J=4.8 Hz), 5.02 (1H, t, J=5.6 Hz), 7.00-7.03 (1H, m), 7.09 (1H,d), 7.20-7.21 (2H, m), 7.77 (1H, d, J=9.2 Hz), 7.99 (1H, d, J=8.8 Hz),8.15 (1H, s), 8.85 (1H, s), 15.30 (1H, s)

MS (ESI): M+ 395

EXAMPLE 3-30

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 2.52 (3H, s), 3.77 (2H, t, J=4.8 Hz),4.01 (2H, s), 4.30 (2H, s), 4.61 (2H, t), 4.90-5.10 (1H, br), 7.03-7.09(2H, m), 7.20-7.26 (7H_(,) m), 7.76 (1H, d), 7.98 (1H, d), 8.17 (1H, s),8.85 (1H, s), 15.30 (1H, s)

MS (ESI): M+ 443

EXAMPLE 3-31

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 2.94 (3H, s), 3.09 (3H, s), 3.75 (2H,m), 4.13-4.18 (1H, m), 4.44-4.48 (1H, m), 4.61 (2H, t), 5.02 (1H, t,J=5.6 Hz), 7.33-7.37 (3H, m), 7.52 (1H, d, J=9.2 Hz), 7.81 (1H, d), 8.01(1H, d, J=8.8 Hz), 8.15 (1H, s), 8.86 (1H, s), 15.27 (1H, s)

MS (ESI): M+ 431

EXAMPLE 3-32

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 1.01 (6H, d), 2.52 (3H, s), 3.12-3.19(1H, m), 3.73-3.75 (2H, m), 4.20 (2H, s), 4.60 (2H, t), 5.02 (1H, t),7.00-7.02 (1H, m), 7.11 (1H, d), 7.19-7.22 (2H, m), 7.77 (1H, d, J=8.8Hz), 7.98 (1H, d, J=9.2 Hz), 8.18 (1H, s), 8.84 (1H, s), 15.31 (1H, s)

MS (ESI): M+ 395

EXAMPLE 3-33

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 1.86 (9H, s), 4.26 (2H, s), 7.22-7.24(1H, m), 7.42-7.49 (2H, m), 7.79 (1H, d, J=9.2 Hz), 8.28 (1H, s), 8.39(1H, d, J=8.8 Hz), 8.98 (1H, s), 15.16 (1H, s)

MS (ESI): M+ 388

EXAMPLE 3-34

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.71 (2H, m), 3.96 (3H, s), 4.21 (2H,s), 4.81 (2H, t), 4.89 (1H, t), 7.19-7.24 (1H, m), 7.40-7.52 (3H, m),7.77 (1H, s), 8.68 (1H, s), 15.17 (1H, s)

MS (ESI): M+ 406

EXAMPLE 3-35

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.75 (2H, m), 4.09 (2H, s), 4.83 (2H,t), 5.33 (1H, t), 5.81 (2H, s), 7.15 (1H, s), 7.15-7.24 (1H, m)r, 7.36(1H, m), 7.48 (1H, m), 7.57 (1H, s), 8.77 (1H, s), 15.37 (1H, s)

MS (ESI): M+ 391

EXAMPLE 3-36

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.79 (2H, t), 4.60 (2H, s), 4.68 (2H,t), 5.05 (1H, t), 7.11 (1H, d, J=6.0 Hz), 7.30-7.34 (1H, m), 7.57 (1H,d, J=6.8 Hz), 8.02 (1H, s), 8.38 (1H, s), 8.95 (1H, s), 13.60-14.00 (1H,br), 14.88 (1H, s)

MS (ESI): M+ 436

EXAMPLE 3-37

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.70-3.72 m), 4.98 (3H, s), 4.23 (2H,s), 4.81 (2H, t), 4.89 (1H, t), 7.20-7.26 (1H, m), 7.50 (1H, s),7.62-7.67 (2H, m), 8.68 (1H, s), 15.10 (1H, s)

MS (ESI): M+ 424

EXAMPLE 3-38

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 2.67 (6H, s), 3.39 (2H, m), 4.21 (2H,s), 4.72 (1H, t), 4.97 (2H, t), 7.20-7.22 (1H, m), 7.40-7.50 (2H, m),7.65 (1H, s), 7.84 (1H, s), 15.10 (1H, s)

MS (ESI): M+ 419

EXAMPLE 3-39

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 2.10 (3H, s), 4.50-4.60 (2H, m), 4.23(2H, s), 4.65 (2H, t), 5.00 (1H, t), 7.20-7.30 (1H, m), 7.40-7.50 (2H,m), 7.65 (1H, s), 8.20 (1H, s), 8.83 (1H, s), 10.20 (1H, s), 15.00 (1H,s)

MS (ESI): M+ 433

EXAMPLE3-40

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.74-3.75 (2H, m), 4.55 (2H, s), 4.65(2H, t), 5.00 (1H, t), 7.17 (1H, d, J=6.3 Hz), 7.34-7.39 (1H, m), 7.62(1H, d, J=6.6 Hz), 7.73 (1H, d, J=9.3 Hz), 8.34 (1H, d, J=9.3 Hz), 8.97(1H, S), 14.62 (1H, s)

MS (ESI): M+ 417

EXAMPLE 3-41

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 1.45 (3H, s), 2.97 (3H, s), 3.74-3.76(2H, m), 4.12 (2H, s), 4.61 (2H, m), 5.03 (1H, t, J=5.6 Hz), 7.24-7.30(1H, m), 7.30-7.39 (3H, m), 7.76 (1H, d), 8.01 (1H, d, J=8.8 Hz), 8.13(1H, s), 8.87 (1H, s), 15.23 (1H, s)

MS (ESI): M+ 395

EXAMPLE 3-42

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.88 (6H, t, J=7.2 Hz), 2.91 (4H, q,J=6.8 Hz), 3.75 (2H, m), 4.23 (2H, s), 4.60 (2H, t), 5.02 (1H, t, J=5.6Hz), 7.00-7.06 (1H, m), 7.14-7.25 (3H, m), 7.77 (1H, d), 7.98 (1H, d,J=8.8 Hz), 8.16 (1H, s), 8.84 (1H, s), 15.32 (1H, s)

MS (ESI): M+ 395

EXAMPLE 3-43

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 1.78 (6H, s), 3.99 (2H, s), 4.25 (2H,s), 4.23 (2H, s), 5.52 (1H, br), 7.20-7.22 (1H, m), 7.42-7.49 (2H, m),7.76 (1H, d, J=9.2 Hz), 8.27 (1H, s), 8.34 (1H, d, J=9.2 Hz), 9.05 (1H,s)

MS (ESI): M+ 404

EXAMPLE 3-44

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 1.36 (3H, t, J=6.9 Hz), 3.70-3.80 (2H,m), 4.12 (2H, s), 4.24 (2H, q, J=7.0 Hz), 4.62 (2H, t), 5.00 (1H, t),7.16-7.27 (3H, m), 7.40-7.50 (1H, m), 8.12 (1H, s), 8.80 (1H, s), 15.50(1H, s)

MS (ESI): M+ 420

EXAMPLE 3-45

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.70-3.80 (2H, m), 3.84 (3H, s), 3.85(3H,s), 4.19 (2H, s), 4.75 (2H, t), 4.92 (1H, t, J=5.6 Hz), 7.21-7.28(2H, m), 7.45-7.50 (1H, m), 7.95 (1H, s), 8.75 (1H, s), 15.09 (1H, s)

MS (ESI): M+ 436

EXAMPLE 3-46

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 2.62 (3H, s), 3.74 (2H, m), 4.02 (2H,s), 4.61 (2H, t), 5.01-(1H, t), 5.50-5.60 (1H, m), 6.30-6.43 (3H, m),6.95-7.01 (1H, m), 7.82 (1H, d), 7.99 (1H, d, J=8.8 Hz), 8.21 (1H, s),8.85 (1H, s), 15.33 (1H, s)

MS (ESI): M+ 353

EXAMPLE 3-47

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 1.42 (3H, t, J=6.8 Hz), 3.70-3.80 (2H,m), 4.20-4.23 (4H, m), 4.84-5.00 (3H, m), 7.20-7.30 (1H, m), 7.40-7.49(3H, m), 7.77 (1H, s), 8.67 (1H, s)

MS (ESI): M+ 420

EXAMPLE. 3-48

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 2.78 (3H, s), 3.60-3.70 (2H, m), 4.16(2H, s), 4.75-4.79 (2H, m), 5.38 (1H, t), 6.20-6.27 (1H, m), 7.07 (1H,s), 7.20-7.23 (1H, m), 7.39-7.49 (3H, m), 8.80 (1H, s), 15.32 (1H, s)

MS (ESI): M+ 405

EXAMPLE 3-49

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.94 (3H, t, J=7.2 Hz), 1.72-1.78 (2H,m), 3.77 (2H, m), 4.13-4.14 (4H, m), 4.62 (2H, t), 5.00 (1H, br),7.12-7.18 (2H, m), 7.26 (1H, s), 7.44-7.46 (1H, m), 8.13 (1H, s), 8.79(1H, s), 15.49 (1H, s)

MS (ESI): M+ 434

EXAMPLE 3-50

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.00 (3H, s), 3.08 (3H, s), 3.75-3.77(2H, m), 4.16 (2H, s), 4.57 (2H, t), 5.00 (1H, t, J=5.6 Hz), 7.09-7.18(2H, m), 7.24 (1H, s), 7.40-7.41 (1H, m), 7.85 (1H, s), 8.01 (1H, s),8.72 (1H, s), 15.67 (1H, s)

MS (ESI): M+ 446

EXAMPLE 3-51

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.72 (3H, s), 3.72-3.80 (2H, m), 3.95(3H, s), 4.06 (2H, s), 4.40-4.50 (2H, m), 5.00 (1H, t), 7.12 (1H, s),7.15-7.19 (2H, m), 7.40-7.45 (1H, m), 7.88 (1H, s), 8.51 (1H, s)

MS (ESI): M+ 420

EXAMPLE 3-52

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.77 (2H, m), 4.17 (2H, s), 4.72 (2H,t, J=4.8 Hz), 4.97 (1H, t, J=5.6 Hz), 7.08 (2H, d, J=7.6 Hz), 7.09-7.2.5(2H, m), 7.31-7.36 (2H, m), 7.43-7.49 (3H, m), 8.04 (1H, s), 7.76 (1H,s), 15.02 (1H, s)

MS (ESI): M+ 468

EXAMPLE 3-53

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 1.24 (6H, d, J=7.2 Hz), 3.75 (2H, t),4.08 (2H, s), 4.61 (2H, t), 4.99-5.04 (2H, m), 7.11-7.20 (2H, m), 7.28(1H, s), 7.43-7.45 (1H, m), 8.17 (1H, s), 8.79 (1H, s), 15.52 (1H, s)

MS (ESI): M+ 434

EXAMPLE 3-54

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.99 (3H, t, J=7.3 Hz), 1.60-1.70 (2H,m), 3.00-3.10 (2H, m), 3.70-3.80 (12H, m), 4.15 (2H, s), 4.82 (2H, t),5.50 (1H, t), 6.20 (1H, t), 7.08 (1H, s), 7.10-7.20 (1H, m), 7.40-7.51(3H, m), 8.78 (1H, s), 15.30-15.40 (1H, br)

MS (ESI): M+ 433

EXAMPLE 3-55

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 1.24 (3H, t, J=6.9 Hz), 3.08 (2H, m),3.71-3.80 (2H, m), 4.15 (2H, s), 4.83 (2H, t), 5.43 (1H, t), 6.21 (1H,t),+7.10 (1H, s), 7.17-7.23 (1H, m), 7.36-7.52 (3H, m), 8.78 (1H, s)

MS (ESI): M+ 419

EXAMPLE 3-56

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 1.53 (3H, d, J=6.8 Hz), 3.72 (2H, m),3.99 (3H, s), 4.21 (2H, s), 5.12 (1H, t), 5.70-5.90 (1H, m), 7.20-7.21(1H, m), 7.40-7.55 (3H, m), 7.76 (1H, s), 8.85 (1H, s), 15.00-15.20 (1H,br)

MS (ESI): M+ 420

EXAMPLE 3-57

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 1.52 (3H, d, J=6.8 Hz), 3.71 (2H, t),4.00 (3H, s), 4.23 (2H, s), 5.10 (1H, t), 5.80-5.90 (1H, m), 7.20-7.30(1H, m), 7.51 (1H, s), 7.60-7.67 (2H, m), 8.85 (1H, s), 14.90-15.10 (1H,br)

MS (ESI): M+ 438

EXAMPLE 3-58

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 1.03 (3H, d, J=8.4 Hz), 1.78-1.87 (2H,m), 3.73-3.75 (2H, m), 4.12 (2H, t), 4.20 (2H, s), 4.85 (2H, t), 4.92(1H, t), 7.20 (1H, m), 7.39-7.51 (3H, m), 7.76 (1H, s), 8.68 (1H, s),15.17 (1H, s)

MS (ESI): M+ 434

EXAMPLE 3-59

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 1.35 (6H, s), 3.72-3.75 (2H, m), 4.20(2H, s), 4.83-4.91 (4H, m), 7.20 (1H, m), 7.39-7.49 (3H, m), 7.74 (1H,s), 8.66 (1H, s), 15.18 (1H, s)

MS (ESI): M+ 434

EXAMPLE 3-60

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.86 (3H, t, J=7.3 Hz), 1.80-2.10 (2H,m), 3.70-3.90: (2H, m), 4.26 (2H, s), 5.00-5.10 (1H, m), 5.17 (1H, t,J=5.4 Hz), 7.19-7.24 (1H, m), 7.39-7.51 (2H, m), 7.84 (1H, d, J=8.8 Hz),8.20 (1H, d, J=8.8 Hz), 8.23 (1H, s), 8.86 (1H, s), 15.24 (1H, s)

MS (ESI): M+ 404

EXAMPLE 3-61

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 1.36 (3H, t, J=6.9 Hz), 1.52 (3H, d,J=6.6 Hz), 3.78-3.80 (2H, m), 4.12 (2H, s), 4.26 (2H, q, J=7.0 Hz),5.21-5.30 (2H, m), 7.16-7.24 (2H, m), 7.40-7.46 (2H, m), 8.14 (1H, s),8.81 (1H, s), 15.40-15.60 (1H, br)

MS (ESI): M+ 434

EXAMPLE 3-62

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 2.88 (6H, s), 3.70-3.80 (2H, m), 4.22(2H, s), 4.60-4.70 (2H, m), 5.05 (1H, t), 7.20-7.31 (3H, m), 7.50-7.60(1H, m), 7.80 (1H, s), 8.78 (1H, s), 15.30-15.40 (1H, br)

MS (ESI): M+ 419

EXAMPLE 3-63

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.90-1.29 (5H, m), 1.62-1.80 (6H, m),3.75-3.78 (2H, m), 3.96 (2H, d, J=10.8 Hz), 4.13 (2H, s), 4.60-4.62 (2H,m), 5.02 (1H, t), 7.06-7.24 (2H, m), 7.14 (1H, s), 7.42-7.44 (1H, m),8.16 (1H, s), 8.79 (1H, s)

MS (ESI): M+ 488

EXAMPLE 3-64

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.85-0.89 (6H, m), 2.96-3.00 (2H, m),3.10-3.20 (2H, m), 3.33-3.40 (2H, m), 4.22 (2H, s), 4.74 (1H, t),5.09-5.10 (2H, m), 7.20 (1H, m), 7.38-7.47 (2H, m), 7.59 (1H, s), 7.89(1H, s), 8.72 (1H, s), 15.08 (1H, s)

MS (ESI): M+ 447

EXAMPLE 3-65

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 2.91 (3H, d, J=4.7 Hz), 3.75-3.81 (2H,m), 4.01 (2H, s), 4.50-4.55 (2H, m), 5.04 (1H, t, J=5.5 Hz), 6.59 (1H,s), 6.60-6.68 (1H, m), 7.15-7.24 (2H, m), 7.51-7.55 (1H, m), 7.63 (1H,s), 8.65 (1H, s), 15.90 (1H, s)

MS (ESI): M+ 405

EXAMPLE 3-66

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 1.91-2.00 (4H, m), 3.40-3.50 (4H, m),3.70-3.81, (2H, m), 4.30 (2H, s), 4.50-4.55 (2 H, m), 5.05(1H, t), 6.87(1H, s), 7.10-7.12 (1H, m), 7.18-7.21 (1H, m), 7.49-7.52 (1H, m), 7.72(1H, s), 8.69 (1H, s), 15.65 (1H, s)

MS (ESI).: M+ 445

EXAMPLE 3-67

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 1.44 (3H, t), 1.55 (3H, d), 3.70-3.77,(2H, m), 4.19 (2H, s), 4.28 (2H, q, J=8.8 Hz), 5.14(1H, t), 5.83-5.90(1H, m), 7.20 (1H, m), 7.39-7.40 (1H, m), 7.48-7.50 (2H, m), 7.75 (1H,s), 8.86 (1H, s), 15.13 (1H, s)

MS (ESI): M+ 434

EXAMPLE 3-68

¹H NMR (DMSO-₆ 300 MHz) (δ) ppm: 0.86 (3H, t, J=7.3 Hz), 1.37 (3H, t,J=6.9 Hz), 1.80-2.00, (2H, m), 3.70-3.90 (2H, m), 4.12 (2H, s),4.20-4.28 (2H, m), 5.00-5.17(2H, m), 7.14-7.30 (2H, m), 7.42-7.49 (2H,m), 8.14 (1H, s), 8.78 (1H, s),15.50 (1H, s)

MS (ESI): M+ 448

EXAMPLE 3-69

¹H NMR (DMSO-₆ 400 MHz) (δ) ppm: 1.09-1.27 (5H, m), 1.68-1.82 (6H, m),3.71-3.73 (2H, m), 3.99 (2H, d, J=5.6 Hz), 4.20 (2H, s), 4.80-4.85 (2H,m), 4.92(1H, t, J=5.6 Hz), 7.20 (1H, m), 7.38-7.40 (1H, m), 7.40-7.53(2H, m), 7.75 (1H, s), 8.68 (1H, s), 15.16 (1H, s)

MS (ESI): M+ 488

EXAMPLE 3-70

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.70 (3H, d, J=6.4 Hz), 1.12 (3H, d,J=6.4 Hz), 2.30-2.40 (1H, m), 3.75-3.78 (1H, m), 3.95-4.00 (1H, m), 4.25(2H, s), 4.80-4.85 (1H, m), 5.18(1H, t), 7.20-7.21 (1H, m), 7.41-7.48(2H, m), 7.84 (1H, d), 8.21 (1H, s), 8.25 (1H, d, J=9.2 Hz), 8.92 (1H,s),15.21 (1H, s)

MS (ESI): M+ 418

EXAMPLE 3-71

¹H NMR (DMSO-₆ 400 MHz) (δ) ppm: 0.85 (3H, d), 0.90 (3H, d), 1.40-1.50(1H, m), 1.80-1.91 (2H, m), 3.71-3.80 (2H, m), 4.25 (2H, s), 5.15-5.20(2H, m), 7.20-7.21 (1H, m), 7.41-7.48 (2H, m), 7.84 (1H, d, J=8.8 Hz),8.22 (1H, s), 8.24 (1H, d, J=8.8 Hz), 8.83 (1H, s),15.20 (1H, s)

MS (ESI): M+ 432

EXAMPLE 3-72

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.86 (3H, t, J=7.3 Hz), 1.23 (6H, m),1.80-2.00 (2H, m), 3.70-3.90 (2H, m), 4.09 (2H, s), 5.00-5.18 (3H, m),7.12-7.21 (2H, m), 7.44-7.47 (2H, m), 8.20 (1H, s), 8.79 (1H, s),15.54(1H, s)

MS (ESI): M+ 462

EXAMPLE 3-73

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.87 (3H, t, J=7.3 Hz), 1.80-2.10 (2H,m), 3.70-3.90 (2H, m), 4.02 (3H, s), 4.11 (2H, s), 5.00-5.19. (2H, m),7.16-7.24 (2H, m), 7.44-7.48 (2H, m), 8.04 (1H, s), 8.78 (1H, s),15.44(1H, s)

MS (ESI): M+ 434

EXAMPLE 3-74

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 1.23 (6H, dx2), 1.51 (3H, d, J=6.6Hz), 3.77 (2H, t), 4.09 (2H, s), 4.90-5.10 (1H, m), 5.19-5.30 (2H, m),7.12-7.21 (2H, m), 7.41-7.47 (2H, m), 8.20 (1H, s), 8.81 (1H, s), 15.55(1H, s)

MS (ESI): M+ 448

EXAMPLE 3-75

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 1.00 (9H, s), 4.07-4.12 (2H, m), 4.30(2H, s), 5.12-5.14 (2H, m), 7.20-7.25 (1H, m), 7.40-7.45 (1H, m),7.51-7.53 (1H, m), 7.87 (1H, d), 8.25 (1H, s), 8.41 (1H, d, J=9.2 Hz),8.85 (1H, s), 15.20-15.21 (1H, br)

MS (ESI): M+ 432

EXAMPLE 3-76

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.70-3.81 (4H, m), 4.15 (2H, s), 4.24(2H, t, J=5.0 Hz), 4.60-4.62 (2H, m), 5.00-5.02 (2H, m), 7.15-7.20 (1H,m), 7.32-7.34 (2H, m), 7.44-7.49 (1H, m), 8.06 (1H, s), 8.79(1H, s),15.48 (1H, s)

MS (ESI): M+ 436

EXAMPLE 3-77

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 1.90-1.92 (2H, m), 3.53-3.54 (2H, m),3.70-3.80 (2H, m), 4.12 (2H, s), 4.20-4.30 (2H, m), 4.60-4.70 (3H, m),5.02 (1H, t), 7.16-7.22 (2H, m), 7.30 (1H, s), 7.40-7.50 (1H, m), 8.11(1H, s), 8.80 (1H, s)

MS (ESI): M+ 450

EXAMPLE 3-78

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.10-3.20 (2H, m), 3.60-3.80 (4H, m),4.15 (2H, s), 4.78-4.85 (3H, m), 5.30-5.40 (1H, m), 6.10-6.20 (1H, m),7.15-7.20 (2H, m), 7.30-7.52 (3H, m), 8.77 (1H, s), 15.33 (1H, s)

MS (ESI): M+ 435

EXAMPLE 3-79

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.89 (3H, t, J=7.4 Hz), 1.90-2.06 (2H,m), 3.70-3.80 (2H, m), 3.99 (3H, s), 4.22 (2H, s), 5.15 (1H, t, J=5.4Hz), 5.70-5.80 (1H, m), 7.19-7.24 (1H, m), 7.38-7.52 (2H, m), 7.55 (1H,s), 7.77 (1H, s), 8.86 (1H, s), 15.12 (1H, s)

MS (ESI): M+ 434

EXAMPLE 3-80

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 1.59 (3H, d, J=7.2 Hz), 2.61 (3H, s),2.80 (3H, s), 4.20 (2H, s), 4.96 (1H, t, J=5.6 Hz), 6.50-6.60 (1H, m),7.19-7.23 (1H, m), 7.40-7.49 (2H, m), 7.60 (1H, s), 7.80 (1H, s), 8.81(1H, s), 15.06 (1H, s)

MS (ESI): M+ 433

EXAMPLE 3-81

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 4.10-4.40 (4H, m), 5.50-5.60 (1H, m),6.20-6.30 (1H, m), 7.19-7.22 (1H, m), 7.30-7.40 (6H, m), 7.40-7.50 (1H,m), 7.77 (1H, d), 8.00 (1H, d), 8.21 (1H, s), 9.03 (1H, s), 15.11 (1H,s)

MS (ESI): M+ 452

EXAMPLE 3-82

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.86 (3H, t), 1.18-1.34 (2H, m),1.8.7-1.98 (2H, m), 3.73-3.84 (2H, m), 4.25 (2H, s), 5.13-5.17 (2H, m),7.21 (1H, m), 7.41-7.48 (2H, m), 7.83 (1H, d, J=8.0 Hz), 8.19 (1H, d),8.22 (1H, s), 8.85 (1H, s), 15.22 (1H, s)

MS (ESI): M+ 418

EXAMPLE 3-83

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.72 (3H, t, J=7.3 Hz), 0.90-1.20 (SH,m), 2.10-2.30 (1H, m), 3.70-3.80 (1H, m), 3.90-4.10 (1H, m), 4.26 (2H,s), 4.90-5.00 (1H, m), 5.10-5.20 (1H, m) 7.20-7.25 (1H, m), 7.40-7.52(2H, m), 7.84 (1H, d, J=7.8 Hz), 8.23 (1H, s), 8.26(1H, d), 8.92 (1H,s), 15.22 (1H, s)

MS (ESI): M+ 432

EXAMPLE 3-84

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 1.54 (3H, d, J=6.6 Hz), 3.81-3.82 (2H,m), 4.02 (3H, s), 4.12 (2H, s), 5.22 (1H, t, J=5.4 Hz), 5.23-5.40 (1H,m), 7.15-7.26 (2H, m), 7.44-7.50 (2H, m), 8.05 (1H, s), 8.82 (1H, s),15.46 (1H, s)

MS (ESI): M-418

EXAMPLE 3-85

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.25-3.38 (2H, m), 3.82-3.89 (2H, m),4.21 (2H, s), 5.27 (1H, t), 5.40-5.50 (1H, m), 7.10-7.21 (6H, m),7.30-7.40 (1H, m), 7.40-7.50 (1H, m), 7.77 (1H, d), 8.14 (1H, d), 8.14(1H, s), 8.96 (1H, s), 15.15 (1H, s)

MS (ESI):.M+ 466

EXAMPLE 3-86

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.70-3.80 (2H, m), 4.42 (2H, s) 4.69(2H, t), 4.95 (1H, t), 7.37-7.42 (1H, m), 7.51 (1H, d, J=6.2 Hz), 7.59(1H, d, J=7.9 Hz), 8.48 (1H, s), 8.99 (1H, s), 9.04 (1H, s), 14.68 (1H,s)

MS (ESI): M+ 393

EXAMPLE 4-1

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.26 (3H, s), 3.74 (2H, m), 4.42 (2H,s), 4.61 (2H, m), 5.09 (1H, br), 7.78 (1H, m), 7.84 (2H, m), 8.04-8.07(2H, m), 8.18 (1H, m), 8.86 (1H, s), 15.19 (1H, s)

MS (ESI):. M+ 435

EXAMPLE 4-2

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.73 (2H, m), 4.23 (2H, s), 4.59 (2H,m), 4.99 (1H, br), 7.20 (1H, m), 7.31-7.34 (2H, m), 7.44 (1H, m), 7.85(1H, m), 8.01 (1H, s), 8.26. (1H, m), 8.85 (1H, s), 15.27 (1H, s)

MS (ESI): M+ 407

EXAMPLE 4-3

¹H NMR (DMSO-d₆ 400 MHZ) (δ) ppm: 1.15 (3H, t, J=7.6 Hz), 2.57 (2H, q,J=7.6 Hz), 3.73 (2H, m), 4.13 (2H, s), 4.59 (2H, m), 4.99 (1H, m), 7.05(2H, m), 7.13 (1H, m), 7.20 (1H, m), 7.81 (1H, m), 7.98 (1H, m), 8.21(1H, s), 8.84 (1H, s), 15.28 (1H, s)

MS (ESI): M+ 351

EXAMPLE 4-4

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 1.07 (3H, t, J=7.53 Hz), 2.58 (2H, q,J=7.53 Hz), 3.76 (2H, m), 4.22 (2H, s), 4.61 (2H, m), 5.02 (1H, m),7.19-7.23 (4H, m), 7.76 (1H, m), 8.01 (1H, m), 8.09 (1H, s), 8.86 (1H,s), 15.26 (1H, s)

MS (ESI): M+ 351

EXAMPLE 4-5

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 2.28(3H, s), 3.75(2H, m), 4.24(2H, s),4.61(2H, m), 5.04(1H, br), 7.13(1H, d, J=8.1 Hz), 7.28-7.36(2H, m),7.81(1H, d, J=6.7 Hz), 8.03(1H, d, J=8.9 Hz), 8.13(1H, s), 8.86(1H, s),15.24(1H, brs)

MS (ESI): M+ 372

EXAMPLE 4-6

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.75 (2H, m), 4.29 (2H, s), 4.62 (2H,m), 5.07 (1H, m), 7.19 (1H, m), 7.40 (1H, m), 7.52 (1H, m), 7.84 (1H,m), 8.05 (1H, m), 8.19 (1H, s), 8.87 (1H, s), 15.20 (1H, s)

MS (ESI): M+ 375

EXAMPLE 4-7

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.75(2H, m), 4.29(2H, s), 4.61(2H, t,J=5.0 Hz), 5.01(2H, t, J=5.4 Hz), 7.45(1H, d), 7.51(1H, d, J=11.2 Hz),7.74(1H, d), 7.84(1H, dd), 8.01(1H, d), 8.15(1H, s), 8.86(1H, s),15.21(1H, brs)

MS (ESI): M+ 436

EXAMPLE 4-8 EXAMPLE 4-9

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.76 (2H, m), 4.34 (2H, s), 4.59 (2H,m), 5.01 (1H, m), 7.37 (2H, m), 7.62 (1H, m), 8.07 (2H, m), 8.88 (1H,s), 14.99 (1H, s)

MS (ESI): M+ 409

EXAMPLE 4-10

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.20(3H, s), 3.74(2H, m), 4.31(2H, s),4.61(2H, t), 5.00(1H, t), 7.55-7.66(2H, m), 7.78(1H, d), 7.84-7.89(2H,m), 8.03(1H, d, J=8.9 Hz), 8.30(1H, s), 8.86(1H, s), 15.27(1H, brs)

MS (ESI): M+ 402

EXAMPLE 4-11

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.75 (2H, m), 4.18 (2H, s), 4.61 (2H,m), 5.02 (1H, m), 6.69 (1H, m), 6.77 (1H, m)), 7.23 (1H, m), 7.80 (1H,m), 8.02 (1H, m), 8.15 (1H, s), 8.86 (1H, s), 9.66 (1H, s), 15.24 (1H,s)

MS (ESI): M+ 373

EXAMPLE 4-12

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 3.75 (2H, m), 4.29 (2H, s), 4.58 (2H,m), 5.00 (1H, s), 7.31 (1H, m), 7.35 (1H, m), 7.58 (1H, m), 7.71 (1H,m), 7.82 (1H, m), 8.86 (1H, s)

MS (ESI): M+ 409

EXAMPLE 4-13

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 1.34 (3H, t, J=6.8 Hz), 3.73 (2H, m),4.00 (2H, q, J=6.8 Hz), 4.09 (2H, s), 4.59 (2H, m), 5.00 (1H, m), 6.89(1H, m), 6.95 (1H, m), 7.19 (1H, m), 7.27 (1H, m), 7.83 (1H, m),7.97,(1H, m), 8.24 (1H, s), 8.84 (1H, s), 15.33 (1H, s)

MS (ESI): M+ 367

EXAMPLE 4-14

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 3.73 (2H, m), 4.06 (2H, s), 4.60 (2H,m), 5.05 (1H, m), 6.74 (1H, m), 6.85 (1H, m), 7.05 (1H, m), 7.14 (1H,m), 7.82 (1H, m), 7.99 (1H, m), 8.19 (1H, s), 8.84 (1H, s), 9.55 (1H,s), 15.34 (1H, s)

MS (ESI): M+ 339

EXAMPLE 4-15

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 2.49 (3H, s), 3.77 (2H, m), 4.27 (2H,s), 4.60 (2H, m), 5.01 (1H, s), 7.17 (1H, m), 7.35 (1H, m), 7.59 (1H,m), 7.78 (1H, s), 7.95 (1H, s), 8.81 (1H, s), 15.22 (1H, s)

MS (ESI): M+ 406

EXAMPLE 4-16

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 1.35 (3H, d), 1.40 (3H, d), 1.54 (3H,d, J=6.8 Hz), 3.72 (2H, m), 4.20 (2H, s), 4.86-4.92 (1H, m), 5.12 (1H,t, J=5.2 Hz), 5.80-5.90 (1H, m), 7.20 (1H, m), 7.39-7.52 (3H, m), 7.74(1H, s), 8.84 (1H, s), 15.13 (1H, s)

MS (ESI): M+ 448

EXAMPLE 4-17

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.89 (3H, t, J=7.2 Hz), 1.35-1.37 (6H,d), 1.88-2.06 (2H, m), 3.73-3.79 (2H, m), 4.20 (2H, s), 4.80-5.00 (1H,m), 5.16 (1H, t), 5.81-5.84 (1H, m), 7.20 (1H, m), 7.40-7.53 (3H, m),7.75 (1H, s), 8.83 (1H, s), 15.09 (1H, s)

MS (ESI): M+ 462

EXAMPLE 4-18

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.80-1.40 (6H, m), 1.40-1.60 (2H, m),1.70-1.80 (1H, m), 1.80-2.10 (2H, m), 3.70-3.80 (1H, m), 3.90-4.00 (1H,m), 4.26 (2H, s), 4.80-5.00 (1H, m), 5.19 (1H, t), 7.22-7.25 (1H, m),7.42-7.49 (2H, m), 7.85 (1H, d), 8.22 (1H, s), 8.26 (1H, d, J=9.1 Hz),8.95 (1H, s)

MS (ESI): M+ 458

EXAMPLE 4-19

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.70 (3H, d, J=6.6 Hz), 1.14 (3H, d,J=6.4 Hz), 1.21-1.24 (6H, m), 2.20-2.40 (1H, m), 3.70-3.80 (1H, m),3.90-4.00 (1H, m), 4.09 (2H, s), 4.80-4.90 (1H, m), 5.00-5.20 (2H, m),7.12-7.22 (2H, m), 7.43-7.47 (2H, m), 8.19 (1H, s), 8.87 (1H, s), 15.51(1H, s)

MS (ESI): M+ 476

EXAMPLE 4-20

¹H NMR (DMSO-d₆ 300 MHZ) (δ) ppm: 0.97 (9H, s), 1.18 (3H, d, J=5.9 Hz),1.26 (3H, d, J=6.0 Hz), 4.04-4.09 (4H, m), 5.09-5.13 (3H, m), 7.12-7.21(2H, m), 7.43-7.51 (2H, m), 8.19 (1H, s), 8.78 (1H, s), 15.46 (1H, s)

MS (ESI): M+ 490

EXAMPLE 4-21

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.89 (3H, t, J=7.6 Hz), 1.44 (3H, t),1.92-2.06 (2H, m), 3.78 (2H, m), 4.19 (2H, s), 4.25 (2H, q), 5.17 (1H,t, 5.6 Hz), 5.78-5.83 (1H,r m), 7.20 (1H, m), 7.39-7.51 (3H, m), 7.76(1H, s), 8.85 (1H, s), 15.11 (1H, s)

MS (ESI): M+ 448

EXAMPLE 4-22

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.80-1.30 (6H, m), 1.50-1.80 (5H, m),1.80-1.90 (2H, m), 3.60-3.80 (2H, m), 4.26 (2H, s), 5.10-5.20 (2H, m),7.22 (1H, m), 7.30-7.50 (2H, m), 7.85 (1H,d), 8.23 (1H, d), 8.23 (1H,s), 8.84 (1H, s), 15.20 (1H, s)

MS (ESI): M+ 472

EXAMPLE 4-23

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.85 (3H, d), 0.91 (3H, d), 1.24-1.27(6H, m), 1.35-1.43 (1H, m), 1.70-1.80 (1H, m), 1.91-1.95 (1H, m),3.75-3.80 (2H, m), 4.08 (2H, s), 5.00-5.10 (1H, m), 5.16-5.19 (2H, m),7.14-7.21 (2H, m), 7.43-7.44 (2H, m), 8.18 (1H, s), 8.79 (1H, s)

MS (ESI): M+ 490

EXAMPLE 4-24

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.72 (3H, d), 1.09 (3H, d), 1.37-1.40(6H, m), 2.35-2.38 (1H, m), 3.77-3.79 (1H, m), 3.91-3.94 (1H, m), 4.20(2H, s), 4.92-4.96 (1H, m), 5.23 (1H, t), 5.74-5.76 (1H, m), 7.21 (1H,m), 7.40-7.53 (3H, m), 7.75 (1H,s), 8.88 (1H, s), 15.08 (1H, s)

MS (ESI): M+ 476

EXAMPLE 4-25

¹H NMR (DMSO-d₆ 400 MHz) (4) ppm: 0.84 (3H, d, J=6.8 Hz), 0.87 (3H, d,J=6.4 Hz), 1.37 (3H, d, J=11.2 Hz), 1.42 (3H, d, J=10.8 Hz), 1.83-1.87(2H, m), 3.79-3.80 (2H, m), 4.20 (2H, s), 4.90-4.96 (1H, m), 5.20 (1H,t) 6.08-6.10 (1H, m), 7.21 (1H, m), 7.39-7.55 (3H, m), 7.75 (1H,s), 8.78(1H, s), 15.08 (1H, s)

MS (ESI): M+ 490

EXAMPLE 4-26

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.91 (9H, s), 1.35 (3H, d), 1.44 (3H,d), 4.02-4.03 (2H, m), 4.20 (2H, s), 4.92-4.95. (1H, m), 5.15 (1H, t),6.43 (1H, t), 7.19-7.21 (1H, m), 7.39-7.48 (2H, m), 7.55 (1H, s), 7.79(1H,s), 8.80 (1H, s), 15.05 (1H, s)

MS (ESI): M+ 490

EXAMPLE 4-27

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.76 (3H, t), 0.97-1.03 (2H, m), 1.12(3H, d), 2.10-2.20 (1H, m), 3.75-3.80 (1H, m), 3.98-4.02 (1H, m), 4.02(3H, s), 4.11 (2H, s), 4.92-4.95 (1H, m), 5.19 (1H, t), 7.16-7.25 (2H,m), 7.44-7.50 (2H, m), 8.02 (1H, s), 8.87 (1H, s), 15.40 (1H, s)

MS (ESI): M+ 462

EXAMPLE 4-28

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.74 (3H, t, J=7.6 Hz), 0.99-1.03 (2H,m), 1.11 (3H, d), 1.37 (3H, t, J=6.8 Hz), 2.10-2.20 (1H, m), 3.70-3.80(1H, m), 3.96-4.00 (1H, m), 4.11 (2H, s), 4.26 (2H, q, J=7.2 Hz),4.92-5.00 (1H, m), 5.18 (1H, t), 7.14-7.18 (1H, m), 7.24-7.25 (1H,m),7.40 (1H, s), 7.44-7.46 (1H, m), 8.12 (1H, s), 8.86 (1H, s), 15.46(1H, s)

MS (ESI): M+ 476

EXAMPLE 4-29

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.89 (3H, t, J=7.3 Hz), 1.98-2.01 (2H,m), 2.70 (3H, s), 3.80-3.90 (2H, m), 4.21 (2H, s), 5.10-5.21 (2H, m),7.15-7.22 (2H, m), 7.49-7.51 (1H, m),7.65 (1H, s), 8.04 (1H, S), 8.84(1H, s), 15.25 (1H, s)

MS (ESI): M+ 450

EXAMPLE 4-30

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.70 (3H, d, J=6.5 Hz), 1.15 (3H, d,J=6.5 Hz), 1.37 (3H, t, J=6.9 Hz), 2.30-2.40 (1H, m), 3.70-3.80(1H, m),3.90-4.00 (1H, m), 4.11 (2H, s), 4.20-4.30 (2H, m), 4.80-4.90 (1H, m),5.18 (1H, t), 7.14-7.20 (1H, m), 7.24-7.26 (1H, m), 7.43-7.49 (2H, m),8.13 (1H, s), 8.87 (1H, s), 15.49 (1H, s)

MS (ESI): M+ 462

EXAMPLE 4-31

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.97 (9H, s), 1.37 (3H, t, J=6.9 Hz),4.02-4.11 (4H, m), 4.25-4.31 (2H, m), 5.10-5.20 (2H, m), 7.14-7.26 (2H,m), 7.44-7.49 (2H, m), 8.12 (1H, s), 8.78 (1H, s), 15.43 (1H, s)

MS (ESI): M+ 476

EXAMPLE 4-32

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.72 (3H, d, J=6.5 Hz), 1.16 (3H, d,J=6.5 Hz), 2.30-2.50 (1H, m), 3.70-3.90 (1H, m),3.90-4.00 (1H, m), 4.03(3H, s), 4.12 (2H, s), 4.80-4.90 (1H, m), 5.19 (1H, t), 7.19-7.25 (2H,m), 7.46-7.51 (2H, m), 8.04 (1H, s), 8.88 (1H, s), 15.44 (1H, s)

MS (ESI).: M+ 448

EXAMPLE 4-33

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.99 (9H, s), 3.99-4.11(7H, m),5.11-5.20 (2H, m), 7.19-7.25 (2H, m), 7.49-7.52 (2H, m), 8.03 (1H, s),8.78 (1H, s), 15.39 (1H, s)

MS (ESI): M+ 462

EXAMPLE 4-34

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.93 (9H, s), 3.90-4.03(5H, m), 4.22(2H, s), 5.10 (1H, t), 6.20 (1H, t), 7.20-7.30 (1H, m), 7.40-7.57 (2H,m), 7.60 (1H, s), 7.79 (1H, s), 8.78 (1H, s), 15.05 (1H, s)

MS (ESI): M+ 462

EXAMPLE 4-35

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.86 (3H, t, J=7.2 Hz), 1.19-1.29 (8H,m), 1.90-1.93 (2H, m), 3.72-3.80 (2H, m), 4.08 (2H, s), 5.02-5.04 (1H,m), 5.10-5.20 (2H, m), 7.11-7.22 (2H, m), 7.43-7.46 (2H, m), 8.18 (1H,s), 8.78 (1H, s), 15.51 (1H, s)

MS (ESI): M+ 476

EXAMPLE 4-36

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.88 (3H, t, J=7.2 Hz), 1.20-1.35 (2H,m), 1.36 (3H, t, J=6.8 Hz), 1.80-2.00 (2H, m), 3.70-3.80 (2H, m), 4.11(2H, s), 4.25 (2H, q, J=7.2 Hz), 5.17-(1H, t, J=5.6 Hz), 7.14-7.18 (1H,m), 7.24-7.26 (1H, m), 7.41 (1H, s), 7.41-7.45 (1H, m), 8.13 (1H, s),8.78 (1H, s), 15.48 (1H, s)

MS (ESI): M+ 462

EXAMPLE 4-37

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.93 (9H, s), 1.49 (3H, t), 4.00 (2H,t, J=6.4 Hz), 4.20 (2H, s), 4.22-4.33 (2H, m), 5.12 (1H, t), 6.36 (1H,t, J=6.8 Hz), 7.21 (1H, m), 7.39-7.48 (2H, m), 7.54 (1H, s), 7.79 (1H,s), 8.79 (1H, s), 15.04 (1H, s)

MS (ESI): M+ 476

EXAMPLE 4-38

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.89 (3H, t, J=8.0 Hz), 1.23-1.40 (2H,m), 1.80-2.00 (2H, m), 3.75-3.90 (2H, m), 4.02 (3H, s), 4.11 (2H, s),5.10-5.21 (2H, m), 7.16-7.24 (2H, m), 7.44-7.49 (2H, m), 8.03 (1H, s),8.80 (1H, s), 15.44 (1H, br)

MS (ESI): M+ 448

EXAMPLE 4-39

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.74 (3H, t, J=7.1 Hz), 0.84-1.24(11H, m), 2.10-2.30 (1H, m), 3.70-3.80 (1H, m), 3.90-4.00 (1H, m), 4.09(2H, s), 4.80-5.17 (3H, m), 7.15-7.22 (2H, m), 7.40-7.50 (2H, m), 8.19(1H, s), 8.87 (1H, s), 15.51 (1H, s)

MS (ESI): M+ 490

EXAMPLE 4-40

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0₈₀-0.89 (1H, m), 1.04-1.30 (11H, m),1.50-1.60 (2H, m), 1.70-1.80 (iH, m), 1.93-2.01 (2H, m), 3.73-3.76 (1H,m), 3.96-4.00 (1H, m), 4.07 (2H, s), 4.80-4.89 (1H, m), 5.00-5.17 (2H,m), 7.12-7.21 (2H, m), 7.40-7.42 (2H, m), 8.17 (1H, s), 8.87 (1H, s)

MS (ESI): M+ 516

EXAMPLE 4-41

¹H NMR. (DMSO-d₆ 300 MHz) (δ) ppm: 0.80-1.30 (6H, m), 1.46 (3H, t, J=6.9Hz), 1.50-1.70 (2H, m), 1.70-1.80 (1H, m),1.90-2.10 (2H, m), 3.70-3.81(1H, m), 3.92-4.00 (1H, m), 4.20 (3H, s), 4.23 (2H, q, J=6.6 Hz), 5.20(1H, t, J=4.8 Hz), 5.70-5.81 (1H, m), 7.19-7.24 (1H, m), 7.38-7.51 (3H,m), 7.77 (1H, s), 8.91 (1H, s), 15.11 (1H, s)

MS (ESI): M+ 502

EXAMPLE 4-42

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.84-1.30 (6H, m), 1.50-1.70 (2H, m),1.70-1.90 (1H, m), 1.94-2.10 (2H, m), 3.70-3.79 (1H, m), 3.90-4.00. (1H,m), 4.03 (3H, s), 4.10 (2H, s), 4.80-5.00 (1H, m), 5.19 (1H, m),7.19-7.30 (2H, m), 7.43-7.48-(2H, m), 8.02 (1H, s), 8.87 (1H, s), 15.45(1H, s)

MS (ESI): M+ 488

EXAMPLE 4-43

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.80-1.00 (1H, m), 1.14-1.28 (5H, m),1.37 (3H, t, J=6.9 Hz), 1.50-1.70 (2H, m), 1.70-1.80 (1H, m), 1.90-2.10(2H, m), 3.70-3.80 (1H, m), 3.90-4.00 (1H, m), 4.11 (2H, s), 4.25(2H,q), 4.80-5.00 (1H, m), 5.18 (1H, m), 7.17-7.26 (2H, m), 7.41-7.47 (2H,m), 8.13 (1H, s), 8.89 (1H, s)

MS (ESI): M+ 502

EXAMPLE 4-44

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.80-1.00 (1H, m), 1.00-1.40 (5H, m),1.50-1.70 (2H, m), 1.70-1.80 (1H, m), 1.90-2.10 (2H, m), 3.70-3.80 (1H,m), 3.90-4.00 (1H, m), 3.98 (3H, s), 4.21(2H, s), 5.20 (1H, m),5.60-5.70 (1H, m), 7.19-7.25 (1H, m), 7.39-7.54 (3H, m), 7.77 (1H, s),8.92 (1H, s)

MS (ESI): M+ 488

EXAMPLE 4-45

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.74 (3H, d, J=4.0 Hz), 1.08 (3H, d,J=8.0 Hz), 1.45 (3H, t, J=8.0 Hz), 2.36-2.40 (2H, m), 3.70-3.80 (1H, m),3.89-3.93 (1H, m), 4.19 (2H, s), 4.26(2H, q, J=8.0 Hz), 5.20 (1H, t,J=8.0 Hz), 5.69-5.73(1H, m), 7.17-7.20 (1H, m), 7.39 (1H, m), 7.48-7.51(2H, m), 7.76 (1H, s), 8.89 (1H, s)

MS (ESI): M+ 462

EXAMPLE 4-46

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.73 (3H, d, J=6.8 Hz), 1.08 (3H, d,J=6.8 Hz), 2.20-2.40 (2H, m), 3.81-3.91 (1H, m), 3.91-3.99 (1H, m), 3.99(3H, s), 4.22 (2H, s), 5.20 (1H, m), 5.55-5.58(1H, m), 7.10-7.22 (1H,m), 7.41-7.55 (3H, m), 7.77 (1H, s), 8.91 (1H, s), 15.09 (1H, s)

MS (ESI): M+ 448

EXAMPLE 4-47

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.85 (3H, d, J=7.3 Hz), 1.10-1.34 (2H,m), 1.33 (6H, d, J=6.0 Hz), 1.70-2.00 (2H, m), 3.75 (2H, m), 4.17(2H,s), 4.80-4.90(1H, m), 5.14 (1H, m), 5.80-6.00(1H,, m), 7.10-7.20 (1H,m), 7.30-7.50 (3H, m), 7.72 (1H, s), 8.80 (1H, s)

MS (ESI): M+ 476

EXAMPLE 4-48

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.89 (3H, t), 1.20-1.40 (2H, m), 1.44(3H, t), 1.80-2.00 (2H, m), 3.78 (2H, m), 4.20 (2H, s), 4.23 (2H, q,J=6.8 Hz), 5.16 (1H, t, J=5.6 Hz), 5.90-5.92(1H, m), 7.15-7.21 (1H, m),7.39-7.52 (3H, m), 7.76 (1H, s), 8.84 (1H, s), 15.10 (1H, s)

MS (ESI): M+ 462

EXAMPLE 4-49

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.89 (3H, t), 1.23-1.35 (2H, m)1.87-1.96. (2H, m), 3.72-3.79 (2H, m), 3.98 (3H, s), 4.21 (2H, s), 5.15(1H, t, J=5.2 Hz), 5.85-5.88(1H, m), 7.15-7.21 (1H, m), 7.39-7.48 (2H,m), 7.54 (1H, s), 7.76 (1H, s), 8.85 (1H, s), 15.10 (1H, s).

MS (ESI): M+ 448

EXAMPLE 4-50

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.80-1.00 (1H, m), 1.11-1.20 (4H, m),1.20-1.30 (1H, m), 1.35 (3H,d), 1.40- (3H, d), 1.55-1.70 (2H, m),1.72-1.80 (1H, m), 1.95-2.10 (2H, m), 3.77-3.79 (1H, m), 3.95-3.98 (1H,m), 4.20 (2H, s), 4.91-4.94 (1H, m), 5.24 (1H, t), 5.81-5.83(1H, m),7.15-7.21 (1H, m), 7.39-7.50 (2H, m), 7.53 (1H, s), 7.74 (1H, s), 8.89(1H, s), 15.09 (1H, s)

MS (ESI): M+ 516

EXAMPLE 4-51

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.91 (9H, s), 1.48 (3H, t, J=6.9 Hz),3.90-4.00 (2H, m), 4.13 (2H, s), 4.22(2H, q, J=7.0 Hz), 4.90-5.00 (1H,m), 6.10-6.20 (1H, m), 7.17-7.22 (1H, m), 7.34-7.36 (2H, m), 7.45-7.50(1H, m), 7.77 (1H, s), 8.75 (1H, s)

MS (ESI): M+ 476

EXAMPLE 4-52

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.93 (9H, s), 3.90-4.02 (2H, m), 4.15(2H, s), 4.80-4.81 (1H, m), 5.05 (1H, m), 7.19-7.21 (1H, m), 7.35-7.40(1H, m), 7.43-7.45 (1H, m), 7.57 (1H, d), 8.01-8.03 (1H, d, J=8.8 Hz),8.12 (1H, s), 8.76 (1H, s)

MS (ESI): M+ 432

EXAMPLE 4-53

¹H NMR (DMSO-d₆ 400 MHz) (δ) ppm: 0.81 (3H, d), 1.20 (3H, d), 2.28-2.41(1H, m), 3.98 (3H, s), 4.00-4.05 (2H, m), 4.08 (2H, 5)1 4.51-4.60 (1H,m), 7.02-7.08 (2H, m), 7.19 (1H, s), 7.28-7.30 (1H, m), 8.15 (1H, s),8.60 (1H, s)

MS (ESI): M+ 448

EXAMPLE 4-54

¹H NMR (DMSO-d₆ 300 MHz) (δ) ppm: 0.95 (9H, s), 3.96 (3H, s), 3.96-4.03(4H, m), 4.83 (1H, m), 5.17 (1H, m), 7.13-7.23 (2H, m), 7.28 (1H, s),7.42-7.47 (1H, m), 7.80 (1H, s), 8.73 (1H, s)

MS (ESI): M+ 462

Sequence Listing Free Text

-   SEQ ID NO:1: Donor+chain for HIV integrase activity determination-   SEQ ID NO:2: Donor−chain for HIV integrase activity determination-   SEQ ID NO:3: Target+chain for HIV integrase activity determination-   SEQ ID NO:4: Target−chain for HIV integrase activity determination

INDUSTRIAL FIELD OF UTILIZATION

As is clear from the above results, the compounds of the presentinvention has high HIV integrase inhibitory activity.

Therefore, the compounds can be useful pharmaceutical agents for theprophylaxis or therapy of AIDS, as anti-HIV agents having HIV integraseinhibitory activity. Moreover, by a combined use with other anti-HIVagents such as protease inhibitors, reverse transcriptase inhibitors andthe like, the compounds can become more effective anti-HIV agents. Sincethe compounds have high inhibitory activity specific for integrases,they can provide safe pharmaceutical agents for human with a fewer sideeffects.

This application is based on patent application Nos. 2002-336843,2003-65807 and 2003-139616 filed in Japan, the contents of which are allhereby incorporated by reference.

1-41. (canceled)
 42. An anti-HIV agent comprising a compound of formula [I] or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient:

wherein ring Cy is a C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A wherein the heterocyclic group is a saturated or unsaturated ring containing, besides carbon atom(s), at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom, group A is a group consisting of cyano group, phenyl group, nitro group, halogen atom, C₁₋₄ alkyl group, halo C₁₋₄ alkyl group, halo C₁₋₄ alkyloxy group, —OR^(a1), —SR^(a1), —NR^(a1)R^(a2), —CONR^(a1)R^(a2), —SO₂NR^(a1)R^(a2), —COR^(a3), —NR^(a1)COR^(a3), —SO₂R^(a3), —NR^(a1)SO₂R^(a3), —COOR^(a1) and —NR^(a2)COOR^(a3) wherein R^(a1) and R^(a2) are the same or different and each is hydrogen atom, C₁₋₄ alkyl group or benzyl group and R^(a3) is C₁₋₄ alkyl group; R¹ is a substituent selected from the following group B or a C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituents selected from halogen atoms and the following group B wherein group B is a group consisting of C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, —OR^(a4), —SR^(a4), —NR^(a4)R^(a5), —CONR^(a4)R^(a5) —SO₂NR^(a4)R^(a5), —COR^(a6), —NR^(a4)COR^(a6), —SO₂R^(a6), —NR^(a4)SO₂R^(a6), —COOR^(a4) and —NR^(a5)COOR^(a6) wherein R^(a4) and R^(a5) are the same or different and each is selected from a hydrogen atom, C₁₋₄ alkyl group, C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, and R^(a6) is selected from a C₁₋₄ alkyl group, C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A; R² is selected from a hydrogen atom or a C₁₋₄ alkyl group; R³¹ is selected from a hydrogen atom, a cyano group, a hydroxy group, an amino group, a nitro group, a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group, a C₁₋₄ alkylsulfanyl group, a halo C₁₋₄ alkyl group or a halo C₁₋₄ alkyloxy group; X is selected from a C—R³² or a nitrogen atom; and Y is selected from a C—R³³ or a nitrogen atom wherein R³² and R³³ are the same or different and each is selected from a hydrogen atom, cyano group, nitro group, halogen atom, C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or, C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituents selected from halogen atom and the above-mentioned group B, —OR^(a7), SR^(a7), —NR^(a7)R^(a8), —NR^(a7)COR^(a9), —COOR^(a10) or —N═CH—NR^(a10)Ra¹¹ wherein R^(a7) and R^(a8) are the same or different and each is selected from a hydrogen atom, group B or C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituents selected from halogen atom and the above-mentioned group B, R^(a9) is selected from C₁₋₄ alkyl group, and R^(a10) and R^(a11) are the same or different and each is selected from a hydrogen atom or C₁₋₄ alkyl group.
 43. The anti-HIV agent of claim 42, wherein X is C—R³² and Y is C—R³³.
 44. The anti-HIV agent of claim 42, wherein ring Cy is

wherein R⁴ and R⁶ are the same or different and each is a substituent selected from the following group A wherein group A is a group consisting of cyano group, phenyl group, nitro group, halogen atom, C₁₋₄ alkyl group, halo C₁₋₄ alkyl group, halo C₁₋₄ alkyloxy group, —OR^(a1), —SR^(a1), —NR^(a1)R^(a2), —CONR ^(a1)R^(a2), —SO₂NR^(a1)R^(a2), —COR^(a3), —NR^(a1)COR^(a3), —SO₂R^(a3), —NR^(a1)SO₂R^(a3), —COOR^(a1) and —NR^(a2)COOR^(a3) wherein R^(a1) and R^(a2) are the same or different and each is selected from a hydrogen atom, C₁₋₄ alkyl group or benzyl group and R^(a3) is C₁₋₄ alkyl group; R⁵ is a substituent selected from hydrogen atom and group A, and R^(a4) and R⁵ may form a fused ring together with a benzene ring they substitute; and m is 0 or an integer of 1 to 3, and when m is 2 or 3, then R⁶ of each m may be the same or different.
 45. The anti-HIV agent of claim 42, wherein R² is a hydrogen atom.
 46. A compound of formula [II] or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof:

wherein R^(a4) and R⁶ are the same or different and each is a substituent selected from the following group A wherein group A is a group consisting of cyano group, phenyl group, nitro group, halogen atom, C₁₋₄ alkyl group, halo C₁₋₄ alkyl group, halo C₁₋₄ alkyloxy group, —OR^(a1), —SR^(a1), —NR^(a1)R^(a2), —CONR ^(a1)R^(a2), —SO₂NR^(a1)R^(a2), —COR^(a3), —NR^(a1)COR^(a3), SO₂R^(a3), —NR^(a1)SO₂R^(a3), —COO R^(a1) and —NR^(a2)COOR^(a3) wherein R^(a1) and R^(a2) are the same or different and each is selected from a hydrogen atom, C₁₋₄ alkyl group or benzyl group and R^(a3) is C₁₋₄ alkyl group; R⁵ is a substituent selected from hydrogen atom and the above-mentioned group A, and R^(a4) and R⁵ may form a fused ring together with a benzene ring they substitute; m is 0 or an integer of 1 to 3, and when m is 2 or 3, then R⁶ of each m may be the same or different; R¹ is a substituent selected from the following group B or a C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituents selected from halogen atom and the following group B wherein group B is a group consisting of C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, heterocyclic group (wherein the heterocyclic group is a saturated or unsaturated ring containing, besides carbon atom(s), at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, —OR^(a4), —SR^(a4), —NR^(a4)R^(a5), —CONR^(a4)R^(a5), —SO₂NR^(a4)R^(a5), COR^(a6), —NR^(a4)COR^(a6), SO₂R^(a6), —NR^(a4)SO₂R^(a6), —COOR^(a4) and —NR^(a5)COOR^(a6) wherein R^(a4) and R^(a5) are the same or different and each is selected from a hydrogen atom, C₁₋₄ alkyl group, C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, and R^(a6) is selected from C₁₋₄ alkyl group, C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A; R³¹ is selected from a hydrogen atom, a cyano group, a hydroxy group, an amino group, a nitro group, a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group, a C₁₋₄ alkylsulfanyl group, a halo C₁₋₄ alkyl group or a halo C₁₋₄ alkyloxy group; and R³² and R³³ are the same or different and each is selected from a hydrogen atom, a cyano group, a nitro group, a halogen atom, a C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, a heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituents selected from halogen atom and the above-mentioned group B, OR^(a7), —SR^(a7), NR^(a7)R^(a8), —NR^(a7)COR^(a9), —COOR^(a10) or —N═CH—NR^(a10)Ra¹¹ wherein R^(a7) and R^(a8) are the same or different and each is selected from a hydrogen atom, group B or C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituents selected from halogen atom and the above-mentioned group B, R^(a9) is C₁₋₄ alkyl group, and R^(a10) and R^(a11) are the same or different and each is selected from a hydrogen atom or C₁₋₄ alkyl group.
 47. The compound of claim 46, wherein R³¹ is selected from a hydrogen atom, a cyano group, a hydroxy group or a C₁₋₄ alkoxy group, or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof.
 48. The compound of claim 47, wherein R³¹ is selected from a hydrogen atom, or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof.
 49. The compound of claim 46, wherein R³² and R³³ are the same or different and each is selected from a hydrogen atom, a cyano group, a halogen atom, a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A wherein the heterocyclic group is a saturated or unsaturated ring containing, besides carbon atom(s), at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom and group A is a group consisting of cyano group, phenyl group, nitro group, halogen atom, C₁₋₄ alkyl group, halo C₁₋₄ alkyl group, halo C₁₋₄ alkyloxy group, —OR^(a1), —SR^(a1), —NR^(a1)R^(a2), —CONR^(a1)R^(a2), SO₂NR^(a1)R^(a2), —COR^(a3), —NR^(a1)COR^(a3), —SO₂R^(a3), —NR^(a1)SO₂R^(a3), —COOR^(a1) and —NR^(a2)COOR^(a3) wherein R^(a1) and R^(a2) are the same or different and each is hydrogen atom, C₁₋₄ alkyl group or benzyl group and R^(a3) is C₁₋₄ alkyl group, a C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituents selected from halogen atom and the following group B wherein group B is a group consisting of C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, —OR⁴, —SR⁴, —NR^(a4)R^(a5), —CONR^(a4)R^(a5)—SO₂NR^(a4)R^(a5), —COR^(a6), —NR^(a4)COR^(a6), —SO₂R^(a6), —NR^(a4)SO₂R^(a6), —COOR^(a4) and —NR^(a5)COOR^(a6) wherein R^(a4) and R^(a5) are the same or different and each is selected from a hydrogen atom, C₁₋₄ alkyl group, C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, and R^(a6) is selected from C₁₋₄ alkyl group, C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, —OR^(a7), SR^(a7), NR^(a7)R^(a8), —NR^(a7)COR^(a9), —COOR^(a10) or —N═CH—NR^(a10)R^(a11) wherein R^(a7) and R^(a8) are the same or different and each is selected from a hydrogen atom, group B or C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituents selected from halogen atom and the above-mentioned group B, R^(a9) is C₁₋₄ alkyl group, and R^(a10) and R^(a11) are the same or different and each is selected from a hydrogen atom or C₁₋₄ alkyl group, or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof.
 50. The compound of claim 46, wherein R³² is selected from a hydrogen atom, a cyano group, a halogen atom, a C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituents selected from halogen atom and the following group B wherein group B is a group consisting of C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, heterocyclic group (wherein the heterocyclic group is a saturated or unsaturated ring containing, besides carbon atom(s), at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, —OR^(a4), —SR^(a4), —NR^(a4)R^(a5), CONR^(a4)R^(a5), —SO₂NR^(a4)R^(a5), —COR^(a6), —NR^(a4)COR^(a6), —SO₂R^(a6), —NR^(a4)SO₂R^(a6), —COOR^(a4) and —NR^(a5)COOR^(a6) wherein R^(a4) and R^(a5) are the same or different and each is selected from a hydrogen atom, C₁₋₄ alkyl group, C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, and R^(a6) is selected from C₁₋₄ alkyl group, C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, —OR^(a7), —SR^(a7), —NR^(a7)R^(a8), —NR^(a7)COR^(a9) or —COOR^(a10) wherein R^(a7) and R^(a8) are the same or different and each is selected from a hydrogen atom, group B or C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituents selected from halogen atom and the above-mentioned group B, R^(a9) is C₁₋₄ alkyl group, and R^(a10) is selected from a hydrogen atom or C₁₋₄ alkyl group, or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof.
 51. The compound of claim 50, wherein R³² is selected from a hydrogen atom, —OR^(a7) or —NR^(a7)R^(a8) wherein R^(a7) and R^(a8) are the same or different and each is selected from a hydrogen atom, group B or C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituents selected from halogen atom and the above-mentioned group B, or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof.
 52. The compound of claim 49, wherein R³³ is selected from a hydrogen atom, a C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituents selected from halogen atom and the following group B wherein group B is a group consisting of C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, heterocyclic group (wherein the heterocyclic group is a saturated or unsaturated ring containing, besides carbon atom(s), at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, —OR^(a4), —SR^(a4), —NR^(a4)R^(a5), —CONR^(a4)R^(a5), —SO₂NR^(a4)R^(a5), —COR^(a6), —NR^(a4)COR^(a6), —SO₂R^(a6), —NR^(a4)SO₂R^(a6), COOR^(a4) and —NR^(a5)COOR^(a6) wherein R^(a4) and R^(a5) are the same or different and each is selected from a hydrogen atom, C₁₋₄ alkyl group, C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, and R^(a6) is selected from C₁₋₄ alkyl group, C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, —OR^(a7) or —NR^(a7)R^(a8) wherein R^(a7) and R^(a8) are the same or different and each is selected from a hydrogen atom, group B or C₁₋₁₀ alkyl group, optionally substituted by 1 to 3 substituents selected from halogen atom and the above-mentioned group B, or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof.
 53. The compound of claim 52, wherein R³³ is selected from a hydrogen atom, —OR^(a7) or —NR^(a7)R^(a8) wherein R^(a7) and R^(a8) are the same or different and each is selected from a hydrogen atom, group B or C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituents selected from halogen atom and the above-mentioned group B, or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof.
 54. The compound of claim 46, wherein R^(a7) and R^(a8) are the same or different and each is selected from a C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituents selected from halogen atom and the following group B wherein group B is a group consisting of C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, heterocyclic group (wherein the heterocyclic group is a saturated or unsaturated ring containing, besides carbon atom(s), at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, —OR^(a4), —SR^(a4), —NR^(a4)R^(a5), —CONR^(a4)R^(a5), —SO₂NR^(a4)R^(a5), —COR^(a6), —NR^(a4)COR^(a6), —SO₂R^(a6), —NR^(a4)SO₂R^(a6), —COOR^(a4) and —NR^(a5)COOR^(a6) wherein R^(a4) and R^(a5) are the same or different and each is selected from a hydrogen atom, C₁₋₄ alkyl group, C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, and R^(a6) is selected from C₁₋₄ alkyl group, C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof.
 55. The compound of claim 46, wherein R^(a4) and R⁵ are the same or different and each is a substituent selected from cyano group, phenyl group, nitro group, halogen atom, C₁₋₄ alkyl group, halo C₁₋₄ alkyl group, halo C₁₋₄ alkyloxy group, —OR^(a1), —SR^(a1), —NR^(a1)R^(a2), —CONR^(a1)R^(a2), —SO₂NR^(a1)R^(a2), —NR^(a1)COR^(a3), SO₂R^(a3), —NR^(a2)COOR^(a3) and —COOR^(a1) wherein R^(a1) and R^(a2) are the same or different and each is hydrogen atom, C₁₋₄ alkyl group or benzyl group, and R^(a3) is C₁₋₄ alkyl group, or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof.
 56. The compound of claim 55, wherein R^(a4) is selected from a phenyl group, a halogen atom, a C₁₋₄ alkyl group, a halo C₁₋₄ alkyloxy group, OR^(a1), —NR^(a1)R^(a2), CONR^(a1)R^(a2), —SO₂NR^(a1)R^(a2), —NR^(a1)COR^(a3), —SO₂R^(a3), NR^(a1)S₂R^(a3) or —COOR^(a1) wherein R^(a1) and R^(a2) are the same or different and each is selected from a hydrogen atom, C₁₋₄ alkyl group or benzyl group, and R^(a3) is C₁₋₄ alkyl group, or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof.
 57. The compound of claim 56, wherein R^(a4) is a halogen atom, or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof.
 58. The compound of claim 46, wherein R⁵ is selected from a hydrogen atom, a cyano group, a phenyl group, a nitro group, a halogen atom, a C₁₋₄ alkyl group, a halo C₁₋₄ alkyl group, —OR^(a1), —SR^(a1), —NR^(a1)R^(a2), —CONR^(a1)R^(a2), —SO₂NR^(a1)R^(a2) or —NR^(a1)COR^(a3) wherein R^(a1) and R^(a2) are the same or different and each is selected from a hydrogen atom, C₁₋₄ alkyl group or benzyl group, and R^(a3) is C₁₋₄ alkyl group, or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof.
 59. The compound of claim 46, wherein R⁶ is a halogen atom, or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof.
 60. The compound of claim 46, wherein m is 0 or 1, or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof.
 61. The compound of claim 46, wherein R¹ is selected from a C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A wherein group A is a group consisting of cyano group, phenyl group, nitro group, halogen atom, C₁₋₄ alkyl group, halo C₁₋₄ alkyl group, halo C₁₋₄ alkyloxy group, —OR^(a1), —SR^(a), —NR^(a1)R^(a2), —CONR^(a1)R^(a2), —SO₂NR^(a1)R^(a2), —COR^(a3), —NR^(a1)COR^(a3), SO₂R^(a3), —NR^(a1)SO₂R^(a3), —COOR^(a1) and —NR^(a2)COOR^(a3) wherein R^(a1) and R^(a2) are the same or different and each is selected from a hydrogen atom, C₁₋₄ alkyl group or benzyl group and R^(a3) is C₁₋₄ alkyl group, a substituent selected from —NR^(a4)R^(a5), —NR^(a4)COR^(a6), —NR^(a4)SO₂R^(a6) and —NR^(a5)COOR^(a6) wherein R^(a4) and R^(a5) are the same or different and each is selected from a hydrogen atom, C₁₋₄ alkyl group, C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or heterocyclic group (wherein the heterocyclic group is a saturated or unsaturated ring containing, besides carbon atom(s), at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, and R^(a6) is selected from C₁₋₄ alkyl group, C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, or a C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituents selected from halogen atom and group B wherein group B is a group consisting of C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, —OR^(a4), —SR^(a4), —NR^(a4)R^(a5), —CONR^(a4)R¹⁵, —SO₂NR^(a4)R^(a5), —COR^(a6), —NR⁴COR^(a6), —SO₂R^(a6), —NR^(a4)SO₂R^(a6), —COOR^(a4) and —NR^(a5)COOR^(a6) (wherein R^(a4), R^(a5), R^(a6) and group A are as defined above), or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof.
 62. The compound of claim 61, wherein R¹ is a C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituents selected from halogen atom and group B wherein group B is a group consisting of C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, —OR^(a4), —SR^(a4), —NR^(a4)R^(a5), —CONR^(a4)R^(a5), —SO₂NR^(a4)R^(a5), —COR^(a6), —NR^(a4)COR^(a6), —SO₂R^(a6), NR^(a4)SO₂R^(a6), —COOR^(a4) and —NR^(a5)COOR^(a6) wherein R^(a4) and R^(a5) are the same or different and each is selected from a hydrogen atom, C₁₋₄ alkyl group, C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, and R^(a6) is selected from C₁₋₄ alkyl group, C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof.
 63. An anti-HIV agent comprising a compound of formula (III) or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient:

wherein ring Cy is a C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A wherein the heterocyclic group is a saturated or unsaturated ring containing, besides carbon atom(s), at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom, group A is a group consisting of cyano group, phenyl group, nitro group, halogen atom, C₁₋₄ alkyl group, halo C₁₋₄ alkyl group, halo C₁₋₄ alkyloxy group, —OR^(a1), —SR^(a1), —NR^(a1)R^(a2), —CONR^(a1)R^(a2), —SO₂NR^(a1)R^(a2), —COR^(a3), NR^(a1)COR^(a3), —SO₂R^(a3), NR^(a1)SO₂R^(a3), —COOR^(a1) and NR^(a2)COOR^(a3) wherein R^(a1) and R^(a2) are the same or different and each is selected from a hydrogen atom or C₁₋₄ alkyl group and R^(a3) is C₁₋₄ alkyl group; R¹ is a substituent selected from the following group B or a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituents selected from halogen atom and the following group B wherein group B is a group consisting of C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, —OR^(a4), —SR^(a4), —NR^(a4)R^(a5), —CONR^(a4)R^(a5), —SO₂NR^(a4)R^(a5), —COR^(a6), NR^(a4)COR^(a6), SO₂R^(a6), NR^(a4)SO₂R^(a6), —COOR^(a4) and —NR^(a5)COOR^(a6) wherein R^(a4) and R^(a5) are the same or different and each is selected from a hydrogen atom, C₁₋₄ alkyl group, C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, and R^(a6) is selected from C₁₋₄ alkyl group, C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A; R² is selected from a hydrogen atom or a C₁₋₄ alkyl group; R³ is selected from a cyano group, a hydroxy group, an amino group, a nitro group, a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group, a C₁₋₄ alkylsulfanyl group, a halo C₁₋₄ alkyl group or a halo C₁₋₄ alkyloxy group; n is selected from 0 or an integer of 1 to 3 and when n is 2 or 3, R³ each may be the same or different.
 64. A pharmaceutical composition comprising a compound according to claim 46, or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 65. An integrase inhibitor comprising a compound according to claim 42, or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof, as an active ingredient.
 66. An antiviral agent comprising a compound according to claim 46, or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof, as an active ingredient.
 67. An anti-HIV agent comprising a compound according to claim 46, or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof, as an active ingredient.
 68. An anti-HIV composition comprising a compound according to claim 42, or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof, and other one or more kinds of anti-HIV active substance as an active ingredient.
 69. An anti-HIV agent comprising a compound according to claim 42, or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof, as an active ingredient, for multiple drug combination therapy with other anti-HIV agent(s).
 70. A method for the prophylaxis or treatment of an HIV infection or AIDS, which comprises administering a compound according to claim 46, or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof to a mammal.
 71. The method according to claim 70, wherein the compound is administered at a dosage ranging from 0.01 mg to 1 g per administration for an adult.
 72. The method according to claim 70, wherein the compound is administered at a dosage for inhibiting activity specific for integrases.
 73. The method for the prophylaxis or treatment of an HIV infection or AIDS according to claim 70, which further comprises administering at least one different anti-HIV active substance to said mammal.
 74. A method for inhibiting integrase, comprising administering a compound according to claim 46 or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof to a mammal.
 75. A method for the prophylaxis or treatment of a retrovirus infection, comprising administering a compound according to claim 46 or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof to a mammal.
 76. An anti-HIV composition comprising a compound according to claim 46 or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 77. A pharmaceutical composition for inhibiting integrase, comprising a compound according to claim 46 or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 78. An antiviral composition comprising a compound according to claim 46 or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 